StemCell Therapy

Over the last several decades, research has greatly increased our understanding of the immune system, genetics, and biology. This research is now showing results in several areas important to rheumatoid arthritis. Scientists are thinking about RA in exciting ways that were not possible years ago.

NIAMS-supported researchers have identified several genetic factors that may make some people more likely to develop rheumatoid arthritis, as well as factors that affect disease severity. Scientists have learned that dozens of genes determine whether a person develops rheumatoid arthritis and how severe the disease will become. Researchers are studying these findings to help identify new treatment approaches for the disease.

Researchers are also investigating the potential connection between health, disease, and the human microbiome, which are microorganisms that inhabit the human body, such as the intestines and the mouth. One study found that the presence of a specific type of gut bacteria correlated with rheumatoid arthritis in newly diagnosed, untreated people. Another study has found that bacteria in the mouth can contribute to the autoimmune RA process, indicating that good dental hygiene is important. More work is being done to understand how bacteria interacts with the immune system in the disease.

NIAMS intramural researchers are studying the natural history of rheumatoid arthritis in children and adults to understand how the disease progresses and affects patient symptoms and functional status.

Investigators are also exploring whether patients with rheumatoid arthritis in remission while taking tumor necrosis factor (TNF) inhibitors can remain in remission after tapering the dose of these medications. Most studies so far suggest that taking them away completely leads to flares. However, researchers are studying and identifying what factors predict who will relapse when treatments are reduced.

Scientists are continuing to understand what happens at the molecular level in rheumatoid arthritis and are working to develop tests that could help diagnose RA earlier and identify patients who would benefit most from specific treatments.

Joint inflammation. NIAMS-funded researchers have determined that joint inflammation can continue in rheumatoid arthritis even after clinical symptoms have eased. This finding may help doctors determine when a patient is truly in remission and can safely stop treatment.

To date, there is still no cure for RA. Researchers continue to identify genes and molecules that contribute to the development and worsening of rheumatoid arthritis and thus are potential targets for new treatments. The path between identifying the molecule and developing a drug that targets it is long and difficult. Fortunately, several new medications for RA have emerged over the past decades that substantially reduce symptoms and damage in rheumatoid arthritis. However, over time, medications may stop working for some people, creating a need for new advanced therapies. Researchers continue to identify more candidate drugs, with hopes that these will have fewer side effects or will cure more patients.

National Institutes of Health Accelerating Medicines Partnership.NIAMS and the National Institute of Allergy and Infectious Diseases are leading the Accelerating Medicines Partnership Autoimmune and Immune-Mediated Diseases (AMP AIM) Program. AMP AIM is a unique publicprivate partnership that aims to characterize the cellular interactions and biological pathways that cause inflammation, injury, abnormal function, and clinical disease in autoimmune diseases such as rheumatoid arthritis.

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Rheumatoid Arthritis: Research & Resources - National Institute of ...

Zimlovisertib and tofacitinib combo effective in treating rheumatoid arthritis: Study  Medical Dialogues

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Zimlovisertib and tofacitinib combo effective in treating rheumatoid arthritis: Study - Medical Dialogues

Enhertu Established as Second-Line Standard in HER2-Positive Gastric Cancer in Phase III Study  Precision Medicine Online

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Enhertu Established as Second-Line Standard in HER2-Positive Gastric Cancer in Phase III Study - Precision Medicine Online

Walking Just 11 Minutes Each Day Could Add Years To Your Life, Says Study. Here's Why It Works.  Women's Health

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Walking Just 11 Minutes Each Day Could Add Years To Your Life, Says Study. Here's Why It Works. - Women's Health

Want to Live Longer? A New Study Says Making This Easy Swap Could Help  Food & Wine

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Want to Live Longer? A New Study Says Making This Easy Swap Could Help - Food & Wine

Abstract

Genomic medicine, which integrates genomics and bioinformatics into clinical care and diagnostics, is transforming healthcare by enabling personalized treatment approaches. Advances in technologies such as DNA sequencing, proteomics, and computational power have laid the foundation for individualized therapies that account for genetic variations influencing disease risk, progression, and treatment response. This review explores the historical milestones leading to current applications of genomic medicine, such as targeted therapies, gene therapies, and precision medicine, in fields including cardiovascular diseases, oncology, and rare genetic disorders. It highlights the use of next-generation sequencing and third-generation sequencing to improve diagnostic accuracy and treatment outcomes, emphasizing the role of genomic data in advancing personalized treatments. Furthermore, emerging therapies such as CRISPR/Cas-based genome editing and adeno-associated viral vectors showcase the potential of gene therapy in addressing complex diseases, including rare genetic disorders. Despite promising advancements, challenges remain in fully integrating genomic medicine into routine clinical practice, including cost barriers, data interpretation complexities, and the need for widespread genomic literacy among healthcare professionals. The future of genomic medicine holds transformative potential for revolutionizing the diagnosis, treatment, and management of both common and rare diseases.

Keywords: cardiology, genomic medicine, genomics

Genomic medicine refers to genomics and bioinformatics in the context of clinical care and diagnostics[1]. The Human Genome Project was an international collaboration with respect to research that attempted to study the entirety of what is known as the human genome. The human genome is roughly 6 billion DNA base pairs in size and to put it succinctly, contains all the code needed to create what we can call a human being. The fact that different DNA variants being dispersed throughout this genome is what makes an individual different from the rest. Likewise, these DNA variants might also be responsible for causing pathologies that manifest during ones lifetime. Some of these variants can be directly responsible for these pathologies while other variants might be an indicator of how an individuals body will react to a certain treatment. This is where personalized medicine tries to enhance the current scope of medicine[2]. In 1953, Watson and Crick published their first paper on the double helix structure of DNA[3]. In the same year, the sequencing of a biological molecule was completed for the first time via a refined partition chromatography method[4]. At the end of the 1960s, RNA sequencing was still ahead of DNA sequencing[5]. By 1979, the idea of shotgun sequencing was proposed which uses bacterial vectors to clone fragments of a DNA molecule, a procedure allowing sequencing of longer DNA molecules in less time[6]. In 1984, the genome of the Epstein-Barr B95-8 strain was determined[7]. Here-on, a myriad of full-genome screening project was launched and succeeded[5]. GenBank, the US National Institute of Health (NIH) sequence database, was founded in 1982[5]. Advancements in microfabrication, imaging, and computational power led to new sequencing methods. These involve preparing a DNA library by fragmenting DNA, attaching adapters, amplifying it, and then sequencing on a flow cell using massive parallel sequencing[8]. Beginning in the 2010s, third-generation sequencing emerged with the ability to sequence single DNA molecules without amplification. These technologies now produce much longer reads than next-generation sequencing (NGS), ranging from several to hundreds of kilobase pairs[5]. Personalized medicine tailors treatment based on individual patient data, such as genomic and biochemical information, due to significant inter-individual variations. Advances in technologies like DNA sequencing and proteomics have highlighted the need for this approach. Future challenges include enhancing the efficiency of patient characterization and developing effective personalized treatments, although universally effective drugs may still be sought but harder to find[9]. The purpose and objective of this review is to explore the role of genomic medicine in advancing personalized treatment and to assess its current applications, benefits, and challenges.

Genomic medicine integrates genomics and bioinformatics into clinical care and diagnostics, ushering in the era of personalized medicine.

With roots in the groundbreaking discoveries of Watson and Crick in 1953 and the Human Genome Project, advancements in DNA sequencing have revolutionized our understanding of human genetic variation and its role in health and disease.

From early RNA sequencing methods to cutting-edge third-generation sequencing, these innovations have enabled longer and more accurate DNA reads, paving the way for tailored treatments. Personalized medicine leverages genomic and biochemical data to address inter-individual variations, optimizing therapeutic outcomes.

Despite its promise, challenges remain in improving patient characterization and creating effective, individualized treatments, highlighting the ongoing need for innovation in genomic medicine. This review evaluates the transformative impact, current applications, and challenges of genomic medicine in advancing personalized care.

DNA, genes, and genomes constitute the fundamental structural components of an organisms biological framework. DNA double helix with structural base pairing is the most widely recognized DNA structure. It is evident from this structure that DNA is structurally dynamic and capable of adopting alternative secondary structures[3]. A genome is an organisms complete set of DNA sequences. Although people in this world may look different, all human genomes are highly similar[10]. It includes all of an organisms genes and non-coding sequences. Most genomes consist of a linear polymer of DNA wrapped around octameric histone protein complexes to generate a chromatin structure resembling beads on a string[11].

Genetic variations are the changes in the DNA sequences that range from single nucleotide changes to large structural alterations. Some human genetic variations are closely related to certain diseases or individual patient responses to certain medications[12], signifying the need of specific treatment options. These variations could be single nucleotide polymorphisms (SNPs); the simplest form of DNA variation which may influence promoter activity (gene expression), messenger RNA (mRNA) conformation (stability), and subcellular localization of mRNAs and/or proteins and hence may produce disease[13], short insertions and deletions (INDELs); the second most common type of genetic variations[14] characterized by addition and removal of small nucleotide sequences within the genome, copy number variations (CNVs) that arise from genomic rearrangements, primarily owing to deletion, duplication, insertion, and unbalanced translocation events[15] etc. Some human genetic variations are closely related to certain diseases or individual patient responses to certain medications[12], which makes it possible to opt for the treatment that brings the best outcome for the patients. For example, in precision medicine, physicians can choose different medications to help their patients quit smoking by examining the patients speed of nicotine metabolization[16]. Recent studies on genetic variation have moved from examining genes tied to rare single-gene disorders such as cystic fibrosis to investigating genes involved in multifactorial diseases such as cancer and cardiovascular disorders. Therefore, studying genetic variations is not only enriching our knowledge of different disease mechanisms but is also modifying our diagnostic and therapeutic approaches.

It is a slow process yet advancement in knowledge is increasing the use of genomic data and genomic medicine in clinical care[17]. Advancement in genetics brings genetic medicine and genetic data into clinical practice improving the diagnosis of rare diseases, illness related risk improvement, and treatment efficiency through advanced measurement and methods[18]. Next-generation sequencing (NGS) has changed the genomics and not only improve the method but also lowering the costs, can perform rapid genome sequencing and has several medical uses[19].

Genetic testing is important for the detection of inherited and acquired disorders, and also for treatment responses. Multiple genetic tests are used including targeted single-gene assays, gene panels, whole-exome sequencing, and whole-genome sequencing. Chromosomal testing use for detecting changes in chromosomes like additional or missing copies and any large segment modifications[20]. Exome sequencing improves genetic diagnosis and aid in the prenatal identification of structural abnormalities or genetic disorder. Combining copy number variant and single nucleotide variant analyses increases accuracy, whereas low-pass genome sequencing provides higher resolution[21]. Combining copy number variant sequencing and karyotyping improves the identification of prenatal pathogenic chromosomal abnormalities, enhancing the accuracy of prenatal diagnosis[22].

Fluorescence in situ hybridization (FISH) used for detection of tumor-specific genetic variations, enhancing diagnosis and treatment[23]. Genetic testing for prostate cancer, especially in metastatic patients, reveals up to 15% of germline mutations. Pre-test counseling covers inherited risk, diagnostic scope, results, and management options, enhancing personalized care with precision medicine[24]. Myeloid neoplasms and acute leukemias resulting from somatic mutations are helped by enhanced genomic testing, like whole-genome sequencing, for accurate diagnosis and evaluation of risk, thus improving personalized treatment and clinical decision-making[25].

Adequate care for epilepsy is difficult due to numerous syndromes and unique responses, however current genetic discoveries have found abnormalities in ion channels and neurotransmitter receptors in many individuals, whole-exome and whole-genome sequencing methods have enhanced our knowledge and led to precision treatment for particular diseases, like Dravet syndrome, pyroxidine-dependent epilepsy, and glucose transporter 1 deficiency[26].

Gene diagnosis in cardiovascular diseases is gaining attention, especially monogenic cardiovascular diseases. These are the diseases that have cardiovascular damage as their phenotype, e.g., cardiomyopathies, cardiac ion channel disease (long QT syndrome, Brugada syndrome, PVTs), inherited hypertension, inherited aortic diseases[27].

There has been established a causal link between risk of DNA methylation at cpg site and various subtypes of CVD, prior MI, atherosclerotic disease in a recent epigenome wide association study (EWAS)[28]. Selenium supplementation has been known to inhibit DNMT2 mediated DNA methylation of glutathione peroxidase 1 gene promoter in cardiomyocytes reducing the reactive oxygen species and toxicity to cardiomyocytes, and thus protecting the heart during its failure[29].

Genetics play an important role in cardiomyopathies. Pathogenic variants in MYH7 gene, MYBPC3 gene are the most common in encoding abnormal sarcomeric proteins causing Hypertrophic cardiomyopathy. TTN gene, LMNA gene are the most commonly implicated genes in dilated cardiomyopathy. DSC2, DSG2 genes are implicated in arrhythmogenic right ventricular cardiomyopathy. Pathological variant genes testing is implicated to improve prognosis via early screening. Screening of first-degree relatives is also implicated via serial ECGs and echocardiography[30].

Familial hypercholesterolemia is associated with genes such as LDLR, APOB, PCSK9, and APOE. Most of them have autosomal dominant variants and increase the risk of coronary artery disease, atherosclerotic disease, peripheral arterial disease. Early genetic detection can modify the course of disease by early interventions like lifestyle modifications, exercise, blood pressure control, early ignition of statins, and PCSK9 inhibitors [31]. Rather than genome sequencing or exome sequencing, capillary electrophoresis sequencing or next-generation sequencing targeted to known FH gene variants provide a more comprehensive result[32].

Molecular pathophysiology of cardiac diseases can encourage preclinical gene therapy. Adeno-associated viral vector helps in introducing therapeutic genes in heart. Sarcoplasmic reticulum Ca2+ ATPase protein delivery has shown promising result in phase 1 trials to improve cardiac function in heart failure. Crispr/Cas based genome engineering has gained wide recognition for treating cardiovascular disease[33].

Ultrasound targeted micro-bubble (UTM) strategy has gained recognition. Particularly, lipid micro-bubble carrying VEGF and stem cell factor has shown to improve myocardial perfusion and ventricular function in patients with MI[34].

Hypertrophy of ventricles has been shown to reverse with UTM mediated delivery of miR-133 in cardiomyocytes[35]. Anterograde arterial infusion has been indicated in patients with unstable and advanced heart failure, retrograde infusion in patients with impaired coronary artery circulation and limited potential for re-vascularization and direct intramyocardial infusion for focal arrhythmia therapy. Intra-coronary delivery of Ad vector encoding beta2 AR percutaneously, in rabbits, has shown to improve global ventricular systolic and contractility performance[33].

Over the past decade recent advances in genomic medicine has enhanced diagnosis and management of neoplastic diseases by knowing underlying molecular process. Cancer genomic profiling has shown to detect gene amplification, gene deletion mutation, gene fusion of the target genes. These results are interpreted extensively and reflected on treatments. Examples of genomic profiling tests are OncoGuide NCC Oncopanel System, FoundationOne CDx Cancer Genomic Profile, Todai OncoPanel, Oncomine Target Test System. The system used for these tests also functions as a companion diagnostic[36].

Targeted therapies and immunotherapies in oncology like monoclonal antibody against HER 2 which is overexpressed in HER2 positive breast cancer has revolutionized treatment[37]. Osmertinib targeted against EGFR-mutated non-small cell lung cancer has drastically improved disease-free survival[38]. In advanced melanoma, Ipilimumab, a monoclonal antibody directed against cytotoxic T-lymphocyte antigen (CTLA-4) has improved survival[39].

Denosumab targeted against nuclear factor -B ligand RANK-L, inhibits osteoclastic activation and prevents further growth in giant cell bone tumor[40]. Avelumab, a PD-1 inhibitor, is successfully used in Merkel cell carcinoma, Urothelial carcinoma and Renal cell carcinoma[41].

Targeted gene therapy can help destroy tumor without being aggressive with therapies. A case report on 56years old man with lung adenocarcinoma.

Patients PD-L1 TPS was 70% and patient was started on pembrolizumab but recurrence was evidenced after 6th cycle[42]. Other therapies also failed and led to side effects. Thereafter, the patient was enrolled in clinical study conducted by Japanese advanced medical treatment system and was found to be positive EGFR L858R-K860I doublet mutation. Treatment with oral osimertinib led to partial remission in just one month. Patient tolerated this drug and no side effects were noted[43].

Sometimes targeted therapy can lead to new gene activation and neoplastic transformation. Targeted therapy against triple negative breast cancer can lead to the development of metastatic malignant melanoma[44]. Secondary tumors and T-cell lymphoma can occur after CAR T-cell therapy. For patients who received axicabtagene ciloleucel therapy for diffuse large b cell lymphoma developed lethal T cell lymphoma[45]. Furthermore, In recent studies rigid extracellular matrix of cells (ECM) has demonstrated increased tumorigenesis. Targeting ECM stiffness, can lead to collagen depletion and has emerged as potential cancer therapy[46].

There are a wide variety of rare unexplained genetic disorders and developmental anomalies. Their apt diagnosis can help the patients understand their condition better. Recent advancements with NGS, which includes whole genome sequencing, whole exam sequencing, whole mtDNA sequencing, targeted exam sequencing and RNA sequencing, has countered the limitations of more traditional methods like Sanger method, karyotyping, and chromosomal arrays for rare genetic diseases[46].

Whole exome sequencing was done on~500000 individuals in UK Biobank that identified about 564 distinct genes that had significant trait associations, e.g., CHD2 with chronic lymphocytic leukemias of b-cell type, COL1A1 with bone disorders, SERPINC1 with coagulation defects, etc.[47,48].

Many Mitochondrial disorders have been linked with mutations in mitochondrial DNA or nuclear DNA using next-generation sequencing, e.g., MT-TL1, MT-TN mutation causing progressive external ophthalmoplegia, KearnsSayre syndrome (KSS) caused by single large-scale deletion[49].

A whole exome sequencing (WES) analysis was conducted in Lebanon for neurological diseases in consanguineous families[50]. Thirty-three gene variations were identified among the pre-screened consanguineous families with neurogenic disorders. Most common mutation was miss-sense mutation[51].

Rare genetic disorders affect millions of people across the globe either causing premature deaths or leaving them with prolonged co-morbidities. Genetic therapies are our first line revolutionary treatment options. Classic example is AAV (Aden-associated virus) gene therapy for Cystic Fibrosis[52].

X-linked Retinitis Pigmentosa, which occurs due to mutation in RPGR gene, is another target for gene therapy. Retina is excellent for non-invasive procedures and it limits the immunological systemic spread[53]. AAV vector mediated gene transfer in Hemophilia A and B can be used as a one-time treatment with factors level lasting for years[54].

Use of more advance lentiviral vectors as gene therapy for Primary immunodeficiency, SCID, Wiskot-Aldrich and other Leukodystrophies has improved the biosafety. There have been promising results for the use of Autologous T-cells as an alternate strategy for Primary immunodeficiencies[55]. Stem cell gene therapy for Fanconis Anemia is another genetic approach that uses corrected stem cells to rapidly improve entire hematopoiesis of patient[56]. SMN2 gene splicing modifiers like Nusinersen and Risdiplam, SMN1gene replacement therapy with Zongelsma is used for Spinal muscular atrophy[46].

CRISPR/CAS therapy is the gene therapy of future. It is going to be the therapy of choice for rare genetic diseases in the next 1520years. The technology is being tested for Thalassemia and Sickle cell Anemia, and is showing great potential[57]. Thus, the use of genomic medicine, specifically the gene therapy is going to revolutionize the way we clinically diagnose and manage rare genetic disorders.

Pharmacogenomics leverages genomic biomarkers to predict individual responses to drug efficacy and toxicity. While factors like disease severity, diet, and other medications also influence drug responses, genetic differences significantly impact drug metabolism and action. Despite the growing body of research, replicating findings remains a challenge. Genome-wide association studies (GWAS) have identified genetic variations associated with psychiatric disorders and drug responses, but most findings lack consistent replication. The FDA includes pharmacogenomics information in drug labels, highlighting its growing recognition. The Clinical Pharmacogenetics Implementation Consortium (CPIC) aims to translate genetic data into clinical practice, providing guidelines for genome-informed prescribing of antidepressants and antipsychotics[58].

Genetic factors significantly influence the metabolism of lamotrigine (LTG), an antiepileptic drug metabolized mainly by UGT enzymes, particularly UGT1A4. Polymorphisms in these enzymes, such as UGT1A4 and UGT2B7, can affect the drugs plasma concentration and efficacy. Additionally, genetic variations in transporters like OCT1 and ABCG2 also play a role in LTG pharmacokinetics, potentially necessitating dosage adjustments for effective treatment. Further research is needed to fully understand these genetic impacts and to optimize individual treatment plans[59].

A 55-year-old clinical molecular geneticist became a patient after a tumor was detected, leading to a diagnosis of estrogen-receptor positive breast cancer. Initially prescribed tamoxifen, she requested CYP2D6 testing due to concerns about genetic factors affecting the drugs efficacy. The test indicated an intermediate metabolizer status, prompting a switch to anastrozole, in line with CPIC guidelines[60].

P2Y12 inhibitors like clopidogrel and prasugrel are metabolized into active forms by CYP enzymes, notably CYP2C19, which affects their efficacy. Carriers of CYP2C19*2 or 3 alleles, which reduce enzyme function, show decreased drug effectiveness and higher cardiovascular risks. Conversely, the CYP2C1917 allele increases enzyme activity, enhancing drug efficacy and sometimes bleeding risk. Other genetic variants, such as ABCB1 c.3435C>T and CES1, also influence drug metabolism but are not routinely tested[61].

This represents substantial improvements in customized care by offering tailored methods according to the specific genetic characteristics of everyone. One of the main advantages is increased diagnostic accuracy. Comprehending genetics differences allows clinicians to properly diagnose disorders that might otherwise be missed using conventional approaches, resulting in more accurate and earlier disease identification[62]. Enhanced therapeutic efficacy and safety are also significant advantages. Personalized plans based on genomic data can assist in selecting the best medications and dosages, lowering adverse drug reactions and enhancing therapeutic success rates[10]. This personalized approach ensures that therapies are both effective and safe for each patient. Furthermore, enhanced patient results and well-being are significant advantages. individualized. Personalized treatments frequently result in better illness management and prognosis, which can benefit overall patient health and longevity[12]. Patients benefit from therapies that are carefully designed to their unique genetics, resulting in speedier recovery times and an and a higher standard of living. However, putting genomic medicine to use offers its own set of obstacles. These include the requirement for vast genetic data, the complexities of interpreting genetic data and moral questions on genetic privacy and prejudice. Despite these difficulties that genomic medicine seems to be a promising topic regarding the future of individualized therapy.

Incorporating genomics into therapeutic practice requires a dependable bioinformatics infrastructure to manage and interpret vast datasets. This involves developing standardized procedures for the purpose of genome sequencing, analysis, and ensuring compatibility with existing electronic health records[63]. Additionally, there is an urgent requirement for medical personnel to receive comprehensive training in genomics to effectively utilize these perspectives on patient care, bridging the gap between advanced technology and practical application[64].

High price of genome sequencing and related technology is a major obstacle to its broad use, even though sequencing costs have dropped over time, it remains prohibitive for many healthcare systems and patients, particularly in low- and middle-income countries[65].

However, ensuring equitable access to these treatments necessitates significant monetary commitment and supportive policies to subsidize costs and integrate genomic medicine into public healthcare systems.

The gathering, storing, and use of genetic information raise substantial privacy concerns. Making sure patient data are securely stored and used in an ethical manner critical to maintaining public trust in genomic medicine[66]. The ethical implications encompass preventing genetic discrimination and managing the potential psychological impact on patients who discover their risks. Rules and regulations must be established to protect peoples genetic information and discuss the ethical ramifications of using genomic data[67].

Regulating and storing genomic data presents tremendous privacy and security concerns since peoples genetic information is considered sensitive. There is adequate legal protection for genomic data for clinical use, especially where the Health Information Portability and Accountability Act (HIPAA) applies. HIPAA outlines the degree of protection provided to such data and restricts access to only personnel in the clinical field. Some states have additional protections, but these vary from state to state, leading to disparities in privacy levels[68].

Genomic data require robust protection from breaches, necessitating strong methods in their storage and transfer. Access to these data must be highly controlled, with monitoring of everyone who seeks access and logging of all actions on the data to properly identify violators. Preventive measures for the protection of genomic data are of utmost importance due to the severe consequences individuals may face from the misuse of their information[68].

Two critical aspects of handling genomic data are consent and confidentiality, aligning with patients concerns about the privacy of their genetic sequences and potential misuse. The Genetic Information Nondiscrimination Act (GINA), signed into law in 2008, addresses discrimination in insurance and employment based on genetic characteristics but does not cover life, disability, or long-term care insurance.

Privacy is paramount; each patient must know how their genetic details will be utilized, where they will be stored, and who will be allowed access. The HIPAA Privacy Rule generally restricts the disclosure of genetic data without the patients consent, though there may be exceptional cases requiring the disclosure to at-risk relatives based on ethical principles. For instance, physicians might encourage patients to disclose genetic risks to their families while respecting patient privacy and legal guidelines[68].

Lack of equal access to genomic testing and personalized treatments is rampant, with minorities, women, rural patients, uninsured/underinsured patients and those with low education and income levels being most affected. For instance, in the case of breast cancer, non-Hispanic Black women receive low rates of BRCA testing compared to non-Hispanic White women. This is partly because there are fewer conversations about genetic testing with healthcare providers and fewer referrals to genetic counselors among minority-serving physicians. Therefore, these disparities also translate to preventive measures, such as lower risk-reducing surgeries among Black women and fewer cases of cascade screening among Black families with BRCA variants. Furthermore, the underserved population, including racial and ethnic minorities, low-income groups, and women, have barriers in accessing treatments such as PCSK9 inhibitors for FH leading to poor cholesterol control and poor health outcomes[69].

In order to improve health equity for genomic medicine it is necessary to engage participants from non-European decent and other deprived population backgrounds. Increasing rates of utilization of genomic services depends on the ability to make such tests accessible and have acceptable coverage in various settings such as community hospitals or primary care physicians offices. Training of the workforce and infrastructure improvement in MSIs aids in improving culturally sensitive care and research. Sparking collaboration with the local communities and the healthcare providers ensures a mutual understanding between the two that will make genomic research to reflect their perception. Furthermore, the financing of the research facilities in other than academic institutions and in underprivileged regions contributes to a wider deployments and participants integration. Together, these strategies seek to address health disparity and guarantee the equitable improvement of all people through genomic medicine[70].

Genetic discrimination focuses on prejudice against people with specific genetic characteristics which exposes them to serious threats such as loss of insurance, inability to secure a job and social exclusion. The following risks have however been regulated by law especially by the Genetic Information Non-discrimination Act of 2008. GINA offers certain federal anti-discrimination provisions for genetic tests whether from the states and health insurers or employers perspectives as they ban such entities from obtaining or using genetic information for underwriting purposes or employment respectively[71]. However, GINA does not cover life, disability or long-term care insurance and for this void state laws try to provide a solution[71].

Some recommendations to address discrimination in genomic medicine are having general statutes such as the Genetic Information Non-discrimination Act, enacted with an aim of preventing discrimination of individuals based on genetic information. In employment and health insurance decisions, GINA is enforced; however, health insurers cannot use genetic information to underwrite life, disability, or long-term care insurance. Furthermore, there are intentions to increase the consciousness about the protection against genetic non-discrimination and to remove the general distrust thereby impeding genomic research due to apprehension for discrimination. Furthermore, the Affordable Care Act (ACA) has also sought to fill gaps by extending provisions that ban the health insurance status discrimination based on pre-existing conditions to include genetic information; thereby supporting GINAs provisions aimed at addressing employment discrimination. Enlarging such protections to encompass all sorts of insurance and ensuring people advocate for a similar system that combines risk might help to avoid discrimination and promote the proper usage of genomic medicine further[72].

Since the Human Genome Projects completion in 2003, DNA sequencing technologies have advanced significantly to fill previously existing gaps[73]. There are primarily two types of DNA sequencing technologies: short-read sequencing and long-read sequencing. Short-read sequencing methods, such as sequence molecule fluorescent sequencing and single-molecule nanopore base sequencing, generate genetic information in 100300 base pairs per read[19]. They are efficient and cost-effective but often miss repetitive regions, duplicated sequences, and complex structural variants, leaving gaps in the data. While long-read sequencing provides better resolution of complex regions and structural variants, it is typically more expensive and has higher error rates. Combining both approaches can enhance genomic analysis[73].

Advancements in pharmacogenomics and the integration of sequenced genomes with medical records, expression profiles, and imaging studies necessitate robust data storage solutions like cloud computing. It is crucial to manage these data while ensuring both accessibility and confidentiality. In the realm of AI, such comprehensive data can significantly enhance the development of genomics and improve outcomes. However, it is vital to apply this knowledge and data judiciously in clinical settings to ensure its effectiveness and ethical use[74,75].

Multi-omics refers to the use of multiple biological omes such as genome, proteome, transcriptome, epigenome, metabolome, radiomics, and microbiome to provide data to achieve a holistic understanding of biological systems and enhance personalized medical treatments[76]. Multi-omics can provide the missing link of information in the study of genomics and help uncover the pathophysiology underlying a disease which will help provide a new approach to its detection, treatment, and prevention[77].This new approach will pave the way for personalized medicine and optimize its clinical outcome based on the uniqueness of an individual[9].

Multi-omics approaches can fill critical gaps in genomic research by providing comprehensive insights into the underlying mechanisms of diseases. By integrating various types of omics data, such as genomics, proteomics, and metabolomics, researchers can better understand disease pathophysiology. This enhanced understanding enables the development of novel strategies for disease detection, treatment, and prevention[77]. The application of these strategies will support the advancement of personalized medicine, which aims to tailor medical interventions to the unique characteristics of each individual. Ultimately, this personalized approach will optimize clinical outcomes and improve patient care by addressing the specific needs and conditions of each patient, leading to more effective and targeted treatments[9].

Precision medicine can categorize individuals based on their clinical features, treatment responses, and prognostic factors[78]. By leveraging multi-omics studies in diseases such as inflammatory bowel disease, various cancers, and lifestyle-related conditions like diabetes, personalized medicine aims to tailor treatments to each persons unique profile. Since pharmacokinetics is closely linked to genetic variations, personalized medicine has the potential to revolutionize genomics and drive the development of new therapies. This approach integrates comprehensive omics data to refine treatment strategies, enhancing their effectiveness and leading to more targeted, individualized healthcare solutions. Ultimately, this method supports more precise and effective management of diverse health conditions, contributing to advancements in medical science and patient care[9].

Artificial intelligence excels at processing multidimentional clinical and biological data, which is critical for precision medicine. It assists in discovering biomarkers via genetic sequencing and other data sources, turning complex data into meaningful insights for tailored treatment strategies[79]. Artificial intelligence algorithms, such as machine learning and deep learning, improve disease daignosis and early detection . This is especially visible in diciplines like oncology and cardiovascular care, where AI helps anticipate disease risk and stratify indiviaduals based on their unique traits[80]. AI gives clinicians additional insight by combining data from many sources, such as electronic health records (EHR), imaging data, and omics data. This integration aids clinical decision-making by increasingthe accuracy of diagnoses and the efficacy of tretmenr strategies[81]. AI is widely employed in oncology for tasks such as tumor identification, therapy planing, and prognosis prediction . It assists in identifying new biomarkers and understanding tumor heterogeneity, resulting in more accurate and effective cancer treatments[82]. AI helps in diagnosis and forecast the prognosis of cardiovascular illnesses. It employs several machine learining models to assess data from EHR, imaging and omics thereby boosting the accuracy of risk prediction and treatment planing[83]. AI has the potential to predict the risks and outcomes of neurodevelopmental diseases by examining genomic variants and other biological markers. However the compexity and variability of these illnesses provide substantial hurdles that AI continues to solve[84].

Personalized medicine in oncology is adapting treatment to individual patient features, especially genomic and molecular markers. This strategy seeks to give the right treatment for the right person at the right time by using genetic information to guide therapeutic decisions[85].

The MINDACT study investigated the use of a 70-gene signature to inform chemotheraphy decisions in early-stage breast cancer.A decision-analytic modeling technique indicates that fewer women may benefit from genomic testing and treatment than previously indicated by the trial, underlining the necessity for personalized decision-making based on genomic risk[86].

The PROMISE study finds that concentrations of hs-cTn and IL-6 were associated with coronary artery disease (CAD) characteristics and major adverse cardiovascular events (MACEs), indicating that myocardial injury and inflamation play a role in CAD pathophysiology. This association was strongest in partipants with non-obstructive CAD, highlighting and opportunity to tailor treatment for this at-risk group[87].

Intensive blood pressure management in older hypertensive persons with sarcopenia was related with a lower risk of cardiovascular disease (CVD) without an increased risk for adverse events, suggesting potential for indivudualized treatment techniques targeted to this at-risk group[88].

STK11/LKB1 mutations were discovered to be a prominent cause of primary resistance to PD-1 inhibitors in KRAS-mutant lung adenocarcinoma (LUAC). This resistance was demonstrated in numerous clinical cohorts, with different response to PD-1 blocking among LUAC subtypes. These findings suggest that STK11/LKB1 mutations can be employed as a predictive biomarker for PD-1 inhibitor efficacy potentially informing customized treatment options for KRAS-mutant patients[89].

KRAS codon G12 mutations have been identified as biomarkers of resistance to trifluidine/tipiracil (FTD/TPI) chemotherapy in metastatic colorectal cancer (mCRC), with patients carrying these mutations showing significantly reduced overall survival benefit from treatment, implying that genomics-based precision medicine could inform chemotherapy selection and improve outcomes for mCRC[90].

The potential of genomics-based tailored treatment, demonstrating that magnesium spplementation can regulate DNA methylation in the TMPRSS2 gene, which is critical for SARS-CoV-2 viral entry. Adjusting magnesium levels in individuals with specific calcium-to-magnesium intake ratios suggests a novel gene-environment interaction that could be leveraged for personalized prevention strategies and treatment of early COVID-19, potentially altering viral susceptibility based on individual genetic and nutritional factors.[91]

Genomic medicine has increased our knowledge of genetic variations, resulting more accurate diagnosis and personalized treatment[18]. DNA sequencing technology, genetic data integration into clinical care, and the use of multi-omics techniques are among the most significant developments.

Future research should focus on increasing access to genetic technology, tackling ethical challenges, and enhancing bioinformatics facilities. Clinical practice needs to change to include these developments, providing fair and efficient individual treatment.

As genomic medicine growing, it will play an increasingly significant part in transforming healthcare. Addressing existing challenges will be important for achieving its full assurance, leading to more customized, precise, and efficient treatments that improves outcomes for patients.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Published online 13 February 2025

Adil Khan, Email: dradilkhan17@gmail.com.

Anchal Ramesh Barapatre, Email: anchalbara15@gmail.com.

Nadir Babar, Email: nadirbabar@gmail.com.

Joy Doshi, Email: joydoshi10@gmail.com.

Mohamd Ghaly, Email: Ghalymohamed587@gmail.com.

Kirtan Ghanshyam Patel, Email: pkirtan099@gmail.com.

Shayan Nawaz, Email: shayan7788@outlook.com.

Uswa Hasana, Email: uswah.2501@gmail.com.

Swara Punit Khatri, Email: khatriswara8@gmail.com.

Shilpa Pathange, Email: Shilpa.pathange27@gmail.com.

Abhinya Reddy Pesaru, Email: abhinya2000@gmail.com.

Chaitanya Swaroop Puvvada, Email: chaitanyaswaroop17@gmail.com.

Marium Billoo, Email: Dr.mariumbilloo@hotmail.com.

Usama Jamil, Email: jamilusama719@gmail.com.

Ethical approval was not required for this review.

Informed consent was not required for this review.

None.

A.K.: conception and design of the study, drafting the manuscript, critical revision of the article for important intellectual content, and final approval of the version to be published. A.R.B.: acquisition of data, analysis and interpretation of data, drafting sections of the manuscript, and revising it critically for important intellectual content. N.B. and C.S.P.: acquisition of data, drafting sections of the manuscript, revising it critically for important intellectual content, and providing final approval of the version to be published. J.D.: assistance in data collection, drafting sections of the manuscript, and revising it critically for important intellectual content. M.G. and S.P.: data interpretation, drafting sections of the manuscript, and revising it critically for important intellectual content. K.G. and M.B.: analysis and interpretation of data, drafting sections of the manuscript, and revising it critically for important intellectual content. S.N.: data collection and interpretation, drafting sections of the manuscript, and revising it critically for important intellectual content. U.H.: assistance in data collection, drafting sections of the manuscript, and revising it critically for important intellectual content. S.P.K. and A.R.P: analysis and interpretation of data, drafting sections of the manuscript, and revising it critically for important intellectual content. U.J.: data collection, drafting sections of the manuscript, and revising it critically for important intellectual content.

The authors declare no conflicts of interest.

None.

Usama Jamil.

None.

None.

This section collects any data citations, data availability statements, or supplementary materials included in this article.

None.

Articles from Annals of Medicine and Surgery are provided here courtesy of Wolters Kluwer Health

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Genomic medicine and personalized treatment: a narrative review

Who Were the Carthaginians? Ancient DNA Study Reveals a Stunning Answer  Haaretz

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Who Were the Carthaginians? Ancient DNA Study Reveals a Stunning Answer - Haaretz

PARIS, FRANCE, 24 April 2025 Ipsen (Euronext: IPN; ADR: IPSEY) will be presenting data from the late-breaking abstract on elafibranor in the investigational Phase II ELMWOOD study at the European Association for the Study of the Liver (EASL) congress as an oral presentation, on 10 May at 11.15 CET. For the first time data highlighting the potential of elafibranor in treating people living with primary sclerosing cholangitis (PSC) will be presented. PSC is a rare liver disease that currently has no approved treatment options.

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Late-breaking elafibranor primary sclerosing cholangitis (PSC) data demonstrates favorable safety profile and significant efficacy in second potential...

Regenerative medicine has the potential to heal or replace tissues and organs damaged by age, disease, or trauma, as well as to normalize congenital defects. Promising preclinical and clinical data to date support the possibility for treating both chronic diseases and acute insults, and for regenerative medicine to abet maladies occurring across a wide array of organ systems and contexts, including dermal wounds, cardiovascular diseases and traumas, treatments for certain types of cancer, and more (13). The current therapy of transplantation of intact organs and tissues to treat organ and tissue failures and loss suffers from limited donor supply and often severe immune complications, but these obstacles may potentially be bypassed through the use of regenerative medicine strategies (4).

The field of regenerative medicine encompasses numerous strategies, including the use of materials and de novo generated cells, as well as various combinations thereof, to take the place of missing tissue, effectively replacing it both structurally and functionally, or to contribute to tissue healing (5). The body's innate healing response may also be leveraged to promote regeneration, although adult humans possess limited regenerative capacity in comparison with lower vertebrates (6). This review will first discuss regenerative medicine therapies that have reached the market. Preclinical and early clinical work to alter the physiological environment of the patient by the introduction of materials, living cells, or growth factors either to replace lost tissue or to enhance the body's innate healing and repair mechanisms will then be reviewed. Strategies for improving the structural sophistication of implantable grafts and effectively using recently developed cell sources will also be discussed. Finally, potential future directions in the field will be proposed. Due to the considerable overlap in how researchers use the terms regenerative medicine and tissue engineering, we group these activities together in this review under the heading of regenerative medicine.

Since tissue engineering and regenerative medicine emerged as an industry about two decades ago, a number of therapies have received Food and Drug Administration (FDA) clearance or approval and are commercially available (Table 1). The delivery of therapeutic cells that directly contribute to the structure and function of new tissues is a principle paradigm of regenerative medicine to date (7, 8). The cells used in these therapies are either autologous or allogeneic and are typically differentiated cells that still maintain proliferative capacity. For example, Carticel, the first FDA-approved biologic product in the orthopedic field, uses autologous chondrocytes for the treatment of focal articular cartilage defects. Here, autologous chondrocytes are harvested from articular cartilage, expanded ex vivo, and implanted at the site of injury, resulting in recovery comparable with that observed using microfracture and mosaicplasty techniques (9). Other examples include laViv, which involves the injection of autologous fibroblasts to improve the appearance of nasolabial fold wrinkles; Celution, a medical device that extracts cells from adipose tissue derived from liposuction; Epicel, autologous keratinocytes for severe burn wounds; and the harvest of cord blood to obtain hematopoietic progenitor and stem cells. Autologous cells require harvest of a patient's tissue, typically creating a new wound site, and their use often necessitates a delay before treatment as the cells are culture-expanded. Allogeneic cell sources with low antigenicity [for example, human foreskin fibroblasts used in the fabrication of wound-healing grafts (GINTUIT, Apligraf) (10)] allow off-the-shelf tissues to be mass produced, while also diminishing the risk of an adverse immune reaction.

Regenerative medicine FDA-approved products

Materials are often an important component of current regenerative medicine strategies because the material can mimic the native extracellular matrix (ECM) of tissues and direct cell behavior, contribute to the structure and function of new tissue, and locally present growth factors (11). For example, 3D polymer scaffolds are used to promote expansion of chondrocytes in cartilage repair [e.g., matrix-induced autologous chondrocyte implantation (MACI)] and provide a scaffold for fibroblasts in the treatment of venous ulcers (Dermagraft) (12). Decellularized donor tissues are also used to promote wound healing (Dermapure, a variety of proprietary bone allografts) (13) or as tissue substitutes (CryoLife and Toronto's heart valve substitutes and cardiac patches) (14). A material alone can sometimes provide cues for regeneration and graft or implant integration, as in the case of bioglass-based grafts that permit fusion with bone (15). Incorporation of growth factors that promote healing or regeneration into biomaterials can provide a local and sustained presentation of these factors, and this approach has been exploited to promote wound healing by delivery of platelet derived growth factor (PDGF) (Regranex) and bone formation via delivery of bone morphogenic proteins 2 and 7 (Infuse, Stryker's OP-1) (16). However, complications can arise with these strategies (Infuse, Regranex black box warning) (17, 18), likely due to the poor control over factor release kinetics with the currently used materials.

The efficacies of regenerative medicine products that have been cleared or approved by the FDA to date vary but are generally better or at least comparable with preexisting products (9). They provide benefit in terms of healing and regeneration but are unable to fully resolve injuries or diseases (1921). Introducing new products to the market is made difficult by the large time and monetary investments required to earn FDA approval in this field. For drugs and biologics, the progression from concept to market involves numerous phases of clinical testing, can require more than a dozen years of development and testing, and entails an average cost ranging from $802 million to $2.6 billion per drug (22, 23). In contrast, medical devices, a broad category that includes noncellular products, such as acellular matrices, generally reach the market after only 37 years of development and may undergo an expedited process if they are demonstrated to be similar to preexisting devices (24). As such, acellular products may be preferable from a regulatory and development perspective, compared with cell-based products, due to the less arduous approval process.

A broad range of strategies at both the preclinical and clinical stages of investigation are currently being explored. The subsequent subsections will overview these different strategies, which have been broken up into three broad categories: (i) recapitulating organ and tissue structure via scaffold fabrication, 3D bioprinting, and self assembly; (ii) integrating grafts with the host via vascularization and innervation; and (iii) altering the host environment to induce therapeutic responses, particularly through cell infusion and modulating the immune system. Finally, methods for exploiting recently identified and developed cell sources for regenerative medicine will be mentioned.

Because tissue and organ architecture is deeply connected with function, the ability to recreate structure is typically believed to be essential for successful recapitulation of healthy tissue (25). One strategy to capture organ structure and material composition in engineered tissues is to decellularize organs and to recellularize before transplantation. Decellularization removes immunogenic cells and molecules, while theoretically retaining structure as well as the mechanical properties and material composition of the native extracellular matrix (26, 27). This approach has been executed in conjunction with bioreactors and used in animal models of disease with lungs, kidneys, liver, pancreas, and heart (25, 2831). Decellularized tissues, without the recellularization step, have also reached the market as medical devices, as noted above, and have been used to repair large muscle defects in a human patient (32). A variation on this approach involves the engineering of blood vessels in vitro and their subsequent decellularization before placement in patients requiring kidney dialysis (33). Despite these successes, a number of challenges remain. Mechanical properties of tissues and organs may be affected by the decellularization process, the process may remove various types and amounts of ECM-associated signaling molecules, and the processed tissue may degrade over time after transplantation without commensurate replacement by host cells (34, 35). The detergents and procedures used to strip cells and other immunogenic components from donor organs and techniques to recellularize stripped tissue before implantation are actively being optimized.

Synthetic scaffolds may also be fabricated that possess at least some aspects of the material properties and structure of target tissue (36). Scaffolds have been fabricated from naturally derived materials, such as purified extracellular matrix components or algae-derived alginate, or from synthetic polymers, such as poly(lactide-coglycolide) and poly(ethylene glycol); hydrogels are composed largely of water and are often used to form scaffolds due to their compositional similarity to tissue (37, 38). These polymers can be engineered to be biodegradable, enabling gradual replacement of the scaffold by the cells seeded in the graft as well as by host cells (39). For example, this approach was used to fabricate tissue-engineered vascular grafts (TEVGs), which have entered clinical trials, for treating congenital heart defects in both pediatric and adult patients (40) (Fig. 1 A and B). It was found using animal models that the seeded cells in TEVGs did not contribute structurally to the graft once in the host, but rather orchestrated the inflammatory response that aided in host vascular cells populating the graft to form the new blood vessel (41, 42). Biodegradable vascular grafts seeded with cells, cultured so that the cells produced extracellular matrix and subsequently decellularized, are undergoing clinical trials in the context of end-stage renal failure (Humacyte) (33). Scaffolds that encompass a wide spectrum of mechanical properties have been engineered both to provide bulk mechanical support to the forming tissue and to provide instructive cues to adherent cells (11). For example, soft fibrincollagen hydrogels have been explored as lymph node mimics (43) whereas more rapidly degrading alginate hydrogels improved regeneration of critical defects in bone (44). In some cases, the polymer's mechanical properties alone are believed to produce a therapeutic effect. For example, injection of alginate hydrogels to the left ventricle reduced the progression of heart failure in models of dilated cardiomyopathy (45) and is currently undergoing clinical trials (Algisyl). Combining materials with different properties can enhance scaffold performance, as was the case of composite polyglycolide and collagen scaffolds that were seeded with cells and served as bladder replacements for human patients (46). In another example, an electrospun nanofiber mesh combined with peptide-modified alginate hydrogel and loaded with bone morphogenic protein 2 improved bone formation in critically sized defects (47). Medical imaging technologies such as computed tomography (CT) and magnetic resonance imaging (MRI) can be used to create 3D images of replacement tissues, sometimes based on the patient's own body (48, 49) (Fig. 1C). These 3D images can then be used as molds to fabricate scaffolds that are tailored specifically for the patient. For example, CT images of a patient were used for fabricating polyurethane and polyethylene-based synthetic trachea, which were then seeded with cells (50). Small building blocks, often consisting of cells embedded in a small volume of hydrogel, can also be assembled into tissue-like structures with defined architectures and cell patterning using a variety of recently developed techniques (51, 52) (Fig. 1D).

Regenerative medicine strategies that recapitulate tissue and organ structure. (A) Scanning electron microscopy image of a TEVG cross-section. Reproduced with permission from ref. 41. (B) Engineered bladder consisting of a polyglycolide and collagen composite scaffold, fabricated based on CT image of patient and seeded with cells. Reproduced with permission from ref. 46. (C) CT image of bone regeneration in critically sized defects without (Left) and with (Right) nanofiber mesh and alginate scaffold loaded with growth factor. Reproduced with permission from ref. 47. (D) Small hydrogel building blocks are assembled into tissue-like structures with microrobots. Reproduced from ref. 52, with permission from Nature Communications. (E) Blueprint for 3D bioprinting of a heart valve using microextrusion printing, with different colors representing different cell types. (F) Printed product. Reproduced with permission from ref. 59. (G) Intestinal crypt stem cells seeded with supporting Paneth cells self-assemble into organoids in culture. Reproduced from ref. 67, with permission from Nature.

Although cell placement within scaffolds is generally poor controlled, 3D bioprinting can create structures that combine high resolution control over material and cell placement within engineered constructs (53). Two of the most commonly used bioprinting strategies are inkjet and microextrusion (54). Inkjet bioprinting uses pressure pulses, created by brief electrical heating or acoustic waves, to create droplets of ink that contains cells at the nozzle (55, 56). Microextrusion bioprinting dispenses a continuous stream of ink onto a stage (57). Both are being actively used to fabricate a wide range of tissues. For example, inkjet bioprinting has been used to engineer cartilage by alternating layer-by-layer depositions of electrospun polycaprolactone fibers and chondrocytes suspended in a fibrincollagen matrix. Cells deposited this way were found to produce collagen II and glycosaminoglycans after implantation (58). Microextrusion printing has been used to fabricate aortic valve replacements using cells embedded in an alginate/gelatin hydrogel mixture. Two cell types, smooth muscle cells and interstitial cells, were printed into two separate regions, comprising the valve root and leaflets, respectively (59) (Fig. 1 E and F). Microextrusion printing of inks with different gelation temperatures has been used to print complex 3D tubular networks, which were then seeded with endothelial cells to mimic vasculature (60). Several 3D bioprinting machines are commercially available and offer different capabilities and bioprinting strategies (54). Although extremely promising, bioprinting strategies often suffer trade-offs in terms of feature resolution, cell viability, and printing resolution, and developing bioprinting technologies that excel in all three aspects is an important area of research in this field (54).

In some situations, it may be possible to engineer new tissues with scaffold-free approaches. Cell sheet technology relies on the retrieval of a confluent sheet of cells from a temperature-responsive substrate, which allows cellcell adhesion and signaling molecules, as well as ECM molecules deposited by the cells themselves, to remain intact (61, 62). Successive sheets can be layered to produce thicker constructs (63). This approach has been explored in a variety of contexts, including corneal reconstruction (64). Autologous oral mucosal cells have been grown into sheets, harvested, and implanted, resulting in reepithelialization of human corneas (64). Autonomous cellular self-assembly may also be used to create tissues and be used to complement bioprinting. For example, vascular cells aggregated into multicellular spheroids were printed in layer-by-layer fashion, using microextrusion, alongside agarose rods; hollow and branching structures that resembled a vascular network resulted after physical removal of the agarose once the cells formed a continuous structure (65). Given the appropriate cues and initial cell composition, even complex structures may form autonomously (66). For example, intestinal crypt-like structures can be grown from a single crypt base columnar stem cell in 3D culture in conjunction with augmented Wnt signaling (67) (Fig. 1G). Understanding the biological processes that drive and direct self-assembly will aid in fully taking advantage of this approach. The ability to induce autonomous self-assembly of the modular components of organs, such as intestinal crypts, kidney nephrons, and lung alveoli, could be especially powerful for the construction of organs with complex structures.

To contribute functionally and structurally to the body, implanted grafts need to be properly integrated with the body. For cell-based implants, integration with host vasculature is of primary importance for graft success (Fig. 2A) (68). Most cells in the body are located within 100 m from the nearest capillary, the distance within which nutrient exchange and oxygen diffusion from the bloodstream can effectively occur (68). To vascularize engineered tissues, the body's own angiogenic response may be exploited via the presentation of angiogenic growth factors (69). A variety of growth factors have been implicated in angiogenesis, including vascular endothelial growth factor (VEGF), angiopoietin (Ang), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) (70, 71). However, application of growth factors may not be effectual without proper delivery modality, due to their short half-life in vivo and the potential toxicity and systemic effects of bolus delivery (45). Sustained release of VEGF, bFGF, Ang, and PDGF leads to robust angiogenic responses and can rescue ischemic limbs from necrosis (45, 72, 73). Providing a sequence of angiogenic factors that first initiate and then promote maturation of newly formed vessels can yield more functional networks (74) (Fig. 2 B and C), and mimicking development via delivery of both promoters and inhibitors of angiogenesis from distinct spatial locations can create tightly defined angiogenic zones (75).

Strategies for vascularizing and innervating tissue-engineered graft. (A) Tissue-engineered graft may be vascularized before implantation: for example, by self-assembly of seeded endothelial cells or by host blood vessels in a process mediated by growth factor release. Compared with bolus injection of VEGF and PDGF (B), sustained release of the same growth factors from a polymeric scaffold (C) led to a higher density of vessels and formation of larger and thicker vessels. Reproduced from ref. 74, with permission from Nature Biotechnology. (D) Scaffold vascularized by being implanted in the omentum before implantation at the injury site. Reproduced with permission from ref. 83. (E) Biodegradable microfluidic device surgically connected to vasculature. Reproduced with permission from ref. 85. Compared with blank scaffold (F), scaffolds delivering VEGF (G) increase innervation of injured skeletal muscle. Reproduced from ref. 97, with permission from Molecular Therapy.

Another approach to promote graft vascularization at the target site is to prevascularize the graft or target site before implantation. Endothelial cells and their progenitors can self-organize into vascular networks when transplanted on an appropriate scaffold (7679). Combining endothelial cells with tissue-specific cells on a scaffold before transplantation can yield tissues that are both better vascularized and possess tissue-specific function (80). It is also possible to create a vascular pedicle for an engineered tissue that facilitates subsequent transplantation; this approach has been demonstrated in the context of both bone and cardiac patches by first placing a scaffold around a large host vessel or on richly vascularized tissue, and then moving the engineered tissue to its final anatomic location once it becomes vascularized at the original site (8183) (Fig. 2D). This strategy was successfully used to vascularize an entire mandible replacement, which was later engrafted in a human patient (84). Microfluidic and micropatterning techniques are currently being explored to engineer vascular networks that can be anastomosed to the femoral artery (85, 86) (Fig. 2E). The site for cell delivery may also be prevascularized to enhance cell survival and function, as in a recent report demonstrating that placement of a catheter device allowed the site to become vascularized due to the host foreign body response to the material; this device significantly improved the efficacy of pancreatic cells subsequently injected into the device (87).

Innervation by the host will also be required for proper function and full integration of many tissues (88, 89), and is particularly important in tissues where motor control, as in skeletal tissue, or sensation, as in the epidermis, provides a key function (90, 91). Innervation of engineered tissues may be induced by growth factors, as has been shown in the induction of nerve growth from mouse embryonic dorsal root ganglia to epithelial tissue in an in vitro model (92). Hydrogels patterned with channels that are subsequently loaded with appropriate extracellular matrices and growth factors can guide nerve growth upon implantation, and this approach has been used to support nerve regeneration after injury (93, 94). Angiogenesis and nerve growth are known to share certain signaling pathways (95), and this connection has been exploited via the controlled delivery of VEGF using biomaterials to promote axon regrowth in regenerating skeletal muscle (96, 97) (Fig. 2 F and G).

Administration of cells can induce therapeutic responses by indirect means, such as secretion of growth factors and interaction with host cells, without significant incorporation of the cells into the host or having the transplanted cells form a bulk tissue (98). For example, infusion of human umbilical cord blood cells can aid in stroke recovery due to enhanced angiogenesis (99), which in turn may have induced neuroblast migration to the site of injury. Similarly, transplanted macrophages can promote liver repair by activating hepatic progenitor cells (100). Transplanted cells can also normalize the injured or diseased environment, by altering the ECM, and improve tissue regeneration via this mechanism. For example, some types of epidermolysis bullosa (EB), a rare genetic skin blistering disorder, are associated with a failure of type VII collagen deposition in the basement membrane. Allogeneic injected fibroblasts were found to deposit type VII collagen deposition, thereby temporarily correcting disease morphology (101). A prototypical example of transplanted cells inducing a regenerative effect is the administration of mesenchymal stem cells (MSCs), which are being widely explored both preclinically and clinically to improve cardiac regeneration after infarction, and to treat graft-versus-host disease, multiple sclerosis, and brain trauma (2, 102) (Fig. 3A). Positive effects of MSC therapy are observed, despite the MSCs being concentrated with some methods of application in the lungs and poor MSC engraftment in the diseased tissue (103). This finding suggests that a systemic paracrine modality is sufficient to produce a therapeutic response in some situations. In other situations, cellcell contact may be required. For example, MSCs can inhibit T-cell proliferation and dampen inflammation, and this effect is believed to at least partially depend on direct contact of the transplanted MSCs with host immune cells (104). Cells are often infused, typically intravenously, in current clinical trials, but cells administered in this manner often experience rapid clearance, which may explain their limited efficacy (105). Immunocloaking strategies, such as with hydrogel encapsulation of both cell suspensions and small cell clusters and hydrogel cloaking of whole organs, can lead to increased cell residency time and delayed allograft rejection (106, 107) (Fig. 3B). Coating infused cells with targeting antibodies and peptides, sometimes in conjunction with lipidation strategies, known as cell painting, has been shown to improve residency time at target tissue site (108). Infused cells can also be modified genetically to express a targeting ligand to control their biodistribution (109).

Illustrations of regenerative medicine therapies that modulate host environment. (A) Injected cells, such as MSCs, can release cytokines and interact with host cells to induce a regenerative response. (B) Polyethylene glycol hydrogel (green) conformally coating pancreatic islets (blue) can support islets after injection. (Scale bar: 200 m.) Reproduced with permission from ref. 107.

Although the goal of regenerative medicine has long been to avoid rejection of the new tissue by the host immune system, it is becoming increasingly clear that the immune system also plays a major role in regulating regeneration, both impairing and contributing to the healing process and engraftment (110, 111). At the extreme end of immune reactions is immune rejection, which is a serious obstacle to the integration of grafts created with allogeneic cells. Immune engineering approaches have shown promise in inducing allograft tolerance: for example, by engineering the responses of immune cells such as dendritic cells and regulatory T cells (112, 113). Changing the properties of implanted scaffolds can also reduce the inflammation that accompanies implantation of a foreign object. For example, decreasing scaffold hydrophobicity and the availability of adhesion ligands can reduce inflammatory responses, and scaffolds with aligned fibrous topography experience less fibrous encapsulation upon implantation (114). Adaptive immune cells may actively inhibit even endogenous regeneration, as shown when depletion of CD8 T cells improved bone fracture healing in a preclinical model (115). Engineering the local immune response may thus allow active promotion of regeneration. For example, the release of cytokines to polarize macrophages to M2 phenotypes, which are considered to be antiinflammatory and proregeneration, was found to increase Schwann cell infiltration and axonal growth in a nerve gap model (116).

Most regenerative medicine strategies rely on an ample cell source, but identifying and obtaining sufficient numbers of therapeutic cells is often a challenge. Stem, progenitor, and differentiated cells derived from both adult and embryonic tissues are widely being explored in regenerative medicine although adult tissue-derived cells are the dominant cell type used clinically to date due to both their ready availability and perceived safety (8). All FDA-approved regenerative medicine therapies to date and the vast majority of strategies explored in the clinic use adult tissue-derived cells. There is great interest in obtaining greater numbers of stem cells from adult tissues and in identifying stem cell populations suitable for therapeutic use in tissues historically thought not to harbor stem cells (117). Basic studies aiming to understand the processes that control stem cell renewal are being leveraged for both purposes, with the prototypical example being studies with hematopoietic stem cells (HSCs) (3). For example, exposure of HSCs in vitro to cytokines that are present in the HSC niche leads to significant HSC expansion, but this increase in number is accompanied by a loss of repopulation potential (118, 119). Coculture of HSCs with cells implicated in the HSC niche and in microenvironments engineered to mimic native bone marrow may improve maintenance of HSC stemness during expansion, enhancing stem cell numbers for transplantation. For example, direct contact of HSCs with MSCs grown in a 3D environment induces greater CD34+ expansion than with MSCs grown on 2D substrate (120). Another example is that culture of skeletal muscle stem cells on substrates with mechanical properties similar to normal muscle leads to greater stem cell expansion (121) and can even rescue impaired proliferative ability in stem cells from aged animals (122).

Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent potentially infinite sources of cells for regeneration and are moving toward clinical use (123, 124). ES cells are derived from blastocyst-stage embryos and have been shown to be pluripotent, giving rise to tissues from all three germ layers (125). Several phase I clinical trials using ES cells have been completed, without reports of safety concerns (Geron, Advanced Cell Technology, Viacyte). iPS cells are formed from differentiated somatic cells exposed to a suitable set of transcription factors that induce pluripotency (126). iPS cells are an attractive cell source because they can be generated from a patient's own cells, thus potentially circumventing the ethical issues of ES and rejection of the transplanted cells (127, 128). Although iPS cells are typically created by first dedifferentiating adult cells to an ES-like state, strategies that induce reprogramming without entering a pluripotent stage have attracted attention due to their quicker action and anticipation of a reduced risk for tumor formation (129). Direct reprogramming in vivo by retroviral injection has been reported to result in greater efficiency of conversion, compared with ex vivo manipulation, and allows in vitro culture and transplantation to be bypassed (130). Strategies developed for controlled release of morphogens that direct regeneration could potentially be adapted for controlling delivery of new genetic information to target cells in vivo, to improve direct reprogramming. Cells resulting from both direct reprogramming and iPS cell differentiation methods have been explored for generating cells relevant to a variety of tissues, including cardiomyocytes, vascular and hematopoietic cells, hepatocytes, pancreatic cells, and neural cells (131). Because ES and iPS cells can form tumors, a tight level of control over the fate of each cell is crucial for their safe application. High-throughput screens of iPS cells can determine the optimal dosages of developmental factors to achieve lineage specification and minimize persistence of pluripotent cells (132). High-throughput screens have also been useful for discovering synthetic materials for iPS culture, which would allow culture in defined, xenogen-free conditions (133). In addition, the same principles used to engineer cellular grafts from differentiated cells are being leveraged to create appropriate microenvironments for reprogramming. For example, culture on polyacrylamide gel substrates with elastic moduli similar to the heart was found to enable longer term survival of iPS-derived cardiomyocytes, compared with other moduli (134). In another study, culture of iPS cell-derived cardiac tissue in hydrogels with aligned fibers, and in the presence of electrical stimulation, enhanced expression of genes associated with cardiac maturation (135).

To date, regenerative medicine has led to new, FDA-approved therapies being used to treat a number of pathologies. Considerable research has enabled the fabrication of sophisticated grafts that exploit properties of scaffolding materials and cell manipulation technologies for controlling cell behavior and repairing tissue. These scaffolds can be molded to fit the patient's anatomy and be fabricated with substantial control over spatial positioning of cells. Strategies are being developed to improve graft integration with the host vasculature and nervous system, particularly through controlled release of growth factors and vascular cell seeding, and the body's healing response can be elicited and augmented in a variety of ways, including immune system modulation. New cell sources for transplantation that address the limited cell supply that hampered many past efforts are also being developed.

A number of issues will be important for the advancement of regenerative medicine as a field. First, stem cells, whether isolated from adult tissue or induced, will often require tight control over their behavior to increase their safety profile and efficacy after transplantation. The creation of microenvironments, often modeled on various stem cell niches that provide specific cues, including morphogens and physical properties, or have the capacity to genetically manipulate target cells, will likely be key to promoting optimal regenerative responses from therapeutic cells. Second, the creation of large engineered replacement tissues will require technologies that enable fully vascularized grafts to be anastomosed with host vessels at the time of transplant, allowing for graft survival. Thirdly, creating a proregeneration environment within the patient may dramatically improve outcomes of regenerative medicine strategies in general. An improved understanding of the immune system's role in regeneration may aid this goal, as would technologies that promote a desirable immune response. A better understanding of how age, disease state, and the microbiome of the patient affect regeneration will likely also be important for advancing the field in many situations (136138). Finally, 3D human tissue culture models of disease may allow testing of regenerative medicine approaches in human biology, as contrasted to the animal models currently used in preclinical studies. Increased accuracy of disease models may improve the efficacy of regenerative medicine strategies and enhance the translation to the clinic of promising approaches (139).

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Regenerative medicine: Current therapies and future ...

Secrets of the Greenland Sharks Longevity Revealed in New Study  The Brighter Side of News

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Secrets of the Greenland Sharks Longevity Revealed in New Study - The Brighter Side of News

Biotech company hoping to revive woolly mammoth, creates woolly mouse: Study  Straight Arrow News

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Biotech company hoping to revive woolly mammoth, creates woolly mouse: Study - Straight Arrow News

Oxford Study Reveals Lifestyle & Environmental Factors Have Greater Impact On Health And Longevity Than  Free Press Journal

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Oxford Study Reveals Lifestyle & Environmental Factors Have Greater Impact On Health And Longevity Than - Free Press Journal

-Interim clinical study updates for the first three Subjects treated with BB-301 in the Phase 1b/2a Clinical Treatment Study to be presented as a late-breaking oral presentation at the 2025 Muscular Dystrophy Association Clinical & Scientific Conference on March 19, 2025- -Interim clinical study updates for the first three Subjects treated with BB-301 in the Phase 1b/2a Clinical Treatment Study to be presented as a late-breaking oral presentation at the 2025 Muscular Dystrophy Association Clinical & Scientific Conference on March 19, 2025-

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Benitec Biopharma Announces Acceptance of Late- Breaking Oral Abstract for the BB-301 Phase 1b/2a Clinical Study at the Muscular Dystrophy Association...

-Fifth Subject in BB-301 Phase 1b/2a Clinical Treatment Study safely treated in February 2025-

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Benitec Biopharma Releases Second Quarter 2025 Financial Results and Provides Operational Update

Incidence of type 2 diabetes and metabolic syndrome by Occupation 10-Year follow-up of the Gutenberg Health Study  BMC Public Health

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Incidence of type 2 diabetes and metabolic syndrome by Occupation 10-Year follow-up of the Gutenberg Health Study - BMC Public Health

'Fix Broken Food System!' Government Urged as Study Says 1 in 5 Brits Affected by Diabetes  Men's Health UK

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'Fix Broken Food System!' Government Urged as Study Says 1 in 5 Brits Affected by Diabetes - Men's Health UK

The data accumulated by scientists of the early 20th century provided compelling evidence that chromosomes are the carriers of genes. But the nature of the genes themselves remained a mystery, as did the mechanism by which they exert their influence. Molecular geneticsthe study of the structure and function of genes at the molecular levelprovided answers to these fundamental questions.

In 1869 Swiss chemist Johann Friedrich Miescher extracted a substance containing nitrogen and phosphorus from cell nuclei. The substance was originally called nuclein, but it is now known as deoxyribonucleic acid, or DNA. DNA is the chemical component of the chromosomes that is chiefly responsible for their staining properties in microscopic preparations. Since the chromosomes of eukaryotes contain a variety of proteins in addition to DNA, the question naturally arose whether the nucleic acids or the proteins, or both together, were the carriers of the genetic information. Until the early 1950s most biologists were inclined to believe that the proteins were the chief carriers of heredity. Nucleic acids contain only four different unitary building blocks, but proteins are made up of 20 different amino acids. Proteins therefore appeared to have a greater diversity of structure, and the diversity of the genes seemed at first likely to rest on the diversity of the proteins.

Evidence that DNA acts as the carrier of the genetic information was first firmly demonstrated by exquisitely simple microbiological studies. In 1928 English bacteriologist Frederick Griffith was studying two strains of the bacterium Streptococcus pneumoniae; one strain was lethal to mice (virulent) and the other was harmless (avirulent). Griffith found that mice inoculated with either the heat-killed virulent bacteria or the living avirulent bacteria remained free of infection, but mice inoculated with a mixture of both became infected and died. It seemed as if some chemical transforming principle had transferred from the dead virulent cells into the avirulent cells and changed them. In 1944 American bacteriologist Oswald T. Avery and his coworkers found that the transforming factor was DNA. Avery and his research team obtained mixtures from heat-killed virulent bacteria and inactivated either the proteins, polysaccharides (sugar subunits), lipids, DNA, or RNA (ribonucleic acid, a close chemical relative of DNA) and added each type of preparation individually to avirulent cells. The only molecular class whose inactivation prevented transformation to virulence was DNA. Therefore, it seemed that DNA, because it could transform, must be the hereditary material.

A similar conclusion was reached from the study of bacteriophages, viruses that attack and kill bacterial cells. From a host cell infected by one bacteriophage, hundreds of bacteriophage progeny are produced. In 1952 American biologists Alfred D. Hershey and Martha Chase prepared two populations of bacteriophage particles. In one population, the outer protein coat of the bacteriophage was labeled with a radioactive isotope; in the other, the DNA was labeled. After allowing both populations to attack bacteria, Hershey and Chase found that only when DNA was labeled did the progeny bacteriophage contain radioactivity. Therefore, they concluded that DNA is injected into the bacterial cell, where it directs the synthesis of numerous complete bacteriophages at the expense of the host. In other words, in bacteriophages DNA is the hereditary material responsible for the fundamental characteristics of the virus.

Today the genetic makeup of most organisms can be transformed using externally applied DNA, in a manner similar to that used by Avery for bacteria. Transforming DNA is able to pass through cellular and nuclear membranes and then integrate into the chromosomal DNA of the recipient cell. Furthermore, using modern DNA technology, it is possible to isolate the section of chromosomal DNA that constitutes an individual gene, manipulate its structure, and reintroduce it into a cell to cause changes that show beyond doubt that the DNA is responsible for a large part of the overall characteristics of an organism. For reasons such as these, it is now accepted that, in all living organisms, with the exception of some viruses, genes are composed of DNA.

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Heredity - DNA, Genes, Inheritance | Britannica

The Department of Genetic Medicine maintains several large centers funded in part by the National Institutes of Health. These research resources have a long history at Johns Hopkins and provide the foundation for innovative research, as well as providing services and information to scientists around the world.

OMIM, is an encyclopedia of genetic disorders, their clinical features and the genes that contribute to them. The database contains information on thousands ofMendelian conditions, disorders caused by errors in a single gene. The database was developed 55years ago by Victor McKusick and is now maintained byAda Hamosh, MD, MPH, and her team. OMIM is used by 2.7 million unique users per year around the world.

GRCFprovides year-roundresearch expertise, products, and services for the study of the human genome. At the leading edge of technology, the GRCF provides sophisticated tools and equipment oftentimes not available in individual research labs. The mission of the GRCF is to provide high quality, cost effective research services and products to investigators throughout the Johns Hopkins scientific community. Accordingly, GRCF services cover a broad segment of genetic research including:

JHG provides research and clinical genotyping and sequencing together with extensive analytic expertise. A partnership between the Departments of Genetic Medicineand Pathology, JHG opened its doors in 2017, co-localizing four existing labs:

CIDR,is a national resource, offering sequencing, genotyping and epigenetic services to scientists looking to discover genes and variants that contribute to human disease. As part of Johns Hopkins Genomics, CIDR researchers focus on the genetic architecture of complex traits, looking at conditions that result from many genetic variants and how these variants accumulate to manifest disease. This includes conditions such as all types of cancer risk, eye diseases, cleft lip and palate, oral health, environmental influences on child health outcomes, ADHD, structural brain disorders, obesity, alcoholism and aging. Most recent studies are focused on minority populations or extremely well-phenotyped populations. CIDR facilitates data cleaning and data sharing. The 140 CIDR studies posted in dbGaP are heavily utilized with > 7,600 data requests. Since opening its doors in 1996, CIDR has been continuously funded by contracts from a consortium of ten National Institutes of Health institutes (the CIDR Program) as well as through funding from many other genomic consortia, including most recently the national precision medicine initiative, the All of Us Research Program. As of January 2024, CIDR has completed 1,508 studies, consisting of > 1.7 million DNA samples and encompassing over 200 different phenotypes for 421 principal investigators world-wide.

BHCMGaccepts samples from thousands of peoplewith rare disorders submitted by a worldwide network of rare-disease experts. A collaboration between Baylor College of Medicine and Johns Hopkins, the goal of the center is to sequence the genomes of people with these conditions as well as appropriate family members to identify the genes and variants responsible for disorders whose molecular basis was previously unknown. In particular, the center seeks families with known or novel conditions for which the culprit gene is unknown. Successful identification of the responsible gene connects a particular gene with a particular set of clinical features, thereby enabling precise molecular diagnosis and prognosis.It alsoinforms research on the development of rational treatment and providing families with information about recurrence risk.

Focused on Kabuki syndrome and related Mendelian disorders of the epigenetic machinery. These rare disorders result from mutations in single genes encoding components of the systems that add, interpret or delete epigenetic marks with the result that sets of genes are mis-regulated. Currently we know of more than 40 such epigenetic disorders, most of which have intellectual disability and growth abnormalities as prominent clinical consequences. By understanding the features and pathogenesis of these precise abnormalities of the epigenetic system IGM investigators expect to understand not only each disorder but also to how the whole epigenetic systems functions and the pathophysiological consequences that accrue when the system malfunctions. This research complements the clinical services offered in the IGM Epigenetics and Chromatin Clinic where patients with these disorders are diagnosed, characterized and treated.

Focused on understanding the molecular pathophysiology of the vascular form of Ehlers-Danlos syndrome (vascular EDS) with the aim of providing informed management of these patients as well as developing new forms of therapy. The Center will utilize advanced genetic and molecular methods to discover the sequence of events that contribute to structural weakening of the arterial wall and internal tissues over time, ultimately leading to tear or rupture and the potential for early death. The research team has developed two mouse models of vascular EDS that demonstrate most of the important physical findings seen in patients with the disorder. As in people with vascular EDS, we observe tremendous variation in the timing of onset and severity of vascular disease in our mouse colonies. Our strong belief is that both genetic and environmental factors have the capacity to afford strong protection in vascular EDS. Once identified, we will attempt to mimic the mechanism of protection using medications or other strategies. The Center also aims to coordinate expert clinical care of individuals with vascular EDS, and to promote research in the clinical sciences that will improve both the length and quality of life for affected individuals. The Center for Vascular Ehlers-Danlos Syndrome Research has received generous and visionary funding from a variety of sources including the EDS Network CARES Foundation, the EDS Today Advocates, the DEFY Foundation, the Aldredge Family Foundation, and the Daskal Family Foundation.

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Research Centers | Johns Hopkins Institute of Genetic Medicine

July 27, 2020, by NCI Staff

CRISPR is a highly precise gene editing tool that is changing cancer research and treatment.

Credit: Ernesto del Aguila III, National Human Genome Research Institute

Ever since scientists realized that changes in DNA cause cancer, they have been searching for an easy way to correct those changes by manipulating DNA. Although several methods of gene editing have been developed over the years, none has really fit the bill for a quick, easy, and cheap technology.

But a game-changer occurred in 2013, when several researchers showed that a gene-editing tool called CRISPR could alter the DNA of human cells like a very precise and easy-to-use pair of scissors.

The new tool has taken the research world by storm, markedly shifting the line between possible and impossible. As soon as CRISPR made its way onto the shelves and freezers of labs around the world, cancer researchers jumped at the chance to use it.

CRISPR is becoming a mainstream methodology used in many cancer biology studies because of the convenience of the technique, said Jerry Li, M.D., Ph.D., of NCIs Division of Cancer Biology.

Now CRISPR is moving out of lab dishes and into trials of people with cancer. In a small study, for example, researchers tested a cancer treatment involving immune cells that were CRISPR-edited to better hunt down and attack cancer.

Despite all the excitement, scientists have been proceeding cautiously, feeling out the tools strengths and pitfalls, setting best practices, and debating the social and ethical consequences of gene editing in humans.

Like many other advances in science and medicine, CRISPR was inspired by nature. In this case, the idea was borrowed from a simple defense mechanism found in some microbes, such as bacteria.

To protect themselves against invaders like viruses, these microbes capture snippets of the intruders DNA and store them away as segments called CRISPRs, or clustered regularly interspersed short palindromic repeats. If the same germ tries to attack again, those DNA segments (turned into short pieces of RNA) help an enzyme called Cas find and slice up the invaders DNA.

After this defense system was discovered, scientists realized that it had the makings of a versatile gene-editing tool. Within a handful of years, multiple groups had successfully adapted the system to edit virtually any section of DNA, first in the cells of other microbes, and then eventually in human cells.

CRISPR consists of a guide RNA (RNA-targeting device, purple) and the Cas enzyme (blue). When the guide RNA matches up with the target DNA (orange), Cas cuts the DNA. A new segment of DNA (green) can then be added.

Credit: National Institute of General Medical Sciences, National Institutes of Health

In the laboratory, the CRISPR tool consists of two main actors: a guide RNA and a DNA-cutting enzyme, most commonly one called Cas9. Scientists design the guide RNA to mirror the DNA of the gene to be edited (called the target). The guide RNA partners with Cas andtrue to its nameleads Cas to the target. When the guide RNA matches up with the target gene's DNA, Cas cuts the DNA.

What happens next depends on the type of CRISPR tool thats being used. In some cases, the target gene's DNA is scrambled while it's repaired, and the gene is inactivated. With other versions of CRISPR, scientists can manipulate genes in more precise ways such as adding a new segment of DNA or editing single DNA letters.

Scientists have also used CRISPR to detect specific targets, such as DNA from cancer-causing viruses and RNA from cancer cells. Most recently, CRISPR has been put to use as an experimental testto detect the novel coronavirus.

Scientists consider CRISPR to be a game-changer for a number of reasons. Perhaps the biggest is that CRISPR is easy to use, especially compared with older gene-editing tools.

Before, only a handful of labs in the world could make the proper tools [for gene editing]. Now, even a high school student can make a change in a complex genome using CRISPR, said Alejandro Chavez, M.D., Ph.D., an assistant professor at Columbia University who has developed several novel CRISPR tools.

CRISPR is also completely customizable. It can edit virtually any segment of DNA within the 3 billion letters of the human genome, and its more precise than other DNA-editing tools.

And gene editing with CRISPR is a lot faster. With older methods, it usually [took] a year or two to generate a genetically engineered mouse model, if youre lucky, said Dr. Li. But now with CRISPR, a scientist can create a complex mouse model within a few months, he said.

Another plus is that CRISPR can be easily scaled up. Researchers can use hundreds of guide RNAs to manipulate and evaluate hundreds or thousands of genes at a time. Cancer researchers often use this type of experiment to pick out genes that might make good drug targets.

And as an added bonus, its certainly cheaper than previous methods, Dr. Chavez noted.

With all of its advantages over other gene-editing tools, CRISPR has become a go-to for scientists studying cancer. Theres also hope that it will have a place in treating cancer, too. But CRISPR isnt perfect, and its downsides have made many scientists cautious about its use in people.

A major pitfall is that CRISPR sometimes cuts DNA outside of the target genewhats known as off-target editing. Scientists are worried that such unintended edits could be harmful and could even turn cells cancerous, as occurred in a 2002 study of a gene therapy.

If [CRISPR] starts breaking random parts of the genome, the cell can start stitching things together in really weird ways, and theres some concern about that becoming cancer, Dr. Chavez explained. But by tweaking the structures of Cas and the guide RNA, scientists have improved CRISPRs ability to cut only the intended target, he added.

Another potential roadblock is getting CRISPR components into cells. The most common way to do this is to co-opt a virus to do the job. Instead of ferrying genes that cause disease, the virus is modified to carry genes for the guide RNA and Cas.

Slipping CRISPR into lab-grown cells is one thing; but getting it into cells in a person's bodyis another story. Some viruses used to carry CRISPR can infect multiple types of cells, so, for instance, they may end up editing muscle cells when the goal was to edit liver cells.

Researchers are exploring different ways to fine-tune the delivery of CRISPR to specific organs or cells in the human body. Some are testing viruses that infect only one organ, like the liver or brain. Others have created tiny structures callednanocapsules that are designed to deliver CRISPR components to specific cells.

Because CRISPR is just beginning to be tested in humans, there are also concerns about how the bodyin particular, the immune systemwill react to viruses carrying CRISPR or to the CRISPR components themselves.

Some wonder whether the immune system could attack Cas (a bacterial enzyme that is foreign to human bodies) and destroy CRISPR-edited cells. Twenty years ago, a patient died after his immune system launched a massive attack against the viruses carrying a gene therapy he had received. However, newer CRISPR-based approaches rely on viruses that appear to be safer than those used for older gene therapies.

Another major concern is that editing cells inside the body could accidentally make changes to sperm or egg cells that can be passed on to future generations. But for almost all ongoing human studies involving CRISPR, patients cells are removed and edited outside of their bodies. This ex vivo approach is considered safer because it is more controlled than trying to edit cells inside the body, Dr. Chavez said.

However, one ongoing study is testing CRISPR gene editing directly in the eyes of people with a genetic disease that causes blindness, called Leber congenital amaurosis.

The first trial in the United States to test a CRISPR-made cancer therapy was launched in 2019 at the University of Pennsylvania. The study, funded in part by NCI, is testing a type of immunotherapy in which patients own immune cells are genetically modified to better see and kill their cancer.

The therapy involves making four genetic modifications to T cells, immune cells that can kill cancer. First, the addition of a synthetic gene gives the T cells a claw-like protein (called a receptor) that sees NY-ESO-1, a molecule on some cancer cells.

Then CRISPR is used to remove three genes: two that can interfere with the NY-ESO-1 receptor and another that limits the cells cancer-killing abilities. The finished product, dubbed NYCE T cells, were grown in large numbers and then infused into patients.

The first trial of CRISPR for patients with cancer tested T cells that were modified to better "see" and kill cancer.CRISPR was used to remove three genes: two that can interfere with the NY-ESO-1 receptor and another that limits the cells cancer-killing abilities.

Credit: National Cancer Institute

We had done a prior study of NY-ESO-1directed T cells and saw some evidence of improved response and low toxicity, said the trials leader, Edward Stadtmauer, M.D., of the University of Pennsylvania. He and his colleagues wanted to see if removing the three genes with CRISPR would make the T cells work even better, he said.

The goal of this study was to first find out if the CRISPR-made treatment was safe. It was tested in two patients with advanced multiple myeloma and one with metastatic sarcoma. All three had tumors that contained NY-ESO-1, the target of the T-cell therapy.

Initial findings suggest that the treatment is safe. Some side effects did occur, but they were likely caused by the chemotherapy patients received before the infusion of NYCE cells, the researchers reported. There was no evidence of an immune reaction to the CRISPR-edited cells.

Only about 10% of the T cells used for the therapy had all four of the desired genetic edits. And off-target edits were found in the modified cells of all three patients. However, none of the cells with off-target edits grew in a way that suggested they had become cancer, Dr. Stadtmauer noted.

The treatment had a small effect on the patients cancers. The tumors of two patients (one with multiple myeloma and one with sarcoma) stopped growing for a while but resumed growing later. The treatment didn't work at all for the third patient.

It'sexciting that the treatment initially worked for the sarcoma patientbecause solid tumors have been a much more difficult nut to crack with cellular therapy," Dr. Stadtmauer said. "Perhaps [CRISPR] techniques will enhance our ability to treat solid tumors with cell therapies.

Although the trial shows that CRISPR-edited cell therapy is possible, the long-term effects still need to be monitored, Dr. Stadtmauer continued. The NYCE cells are safe for as long as weve been watching [the study participants]. Our plan is to keep monitoring them for years, if not decades, he said.

While the study of NYCE T cells marked the first trial of a CRISPR-based cancer treatment, there are likely more to come.

This [trial] was really a proof-of-principle, feasibility, and safety thing that now opens up the whole world of CRISPR editing and other techniques of [gene] editing to hopefully make the next generation of therapies, Dr. Stadtmauer said.

Other clinical studies of CRISPR-made cancer treatments are already underway. A few trials are testing CRISPR-engineered CAR T-cell therapies, another type of immunotherapy. For example, one company is testing CRISPR-engineered CAR T cells in people with B cell cancers and people with multiple myeloma.

There are still a lot of questions about all the ways that CRISPR might be put to use in cancer research and treatment. But one thing is for certain: The field is moving incredibly fast and new applications of the technology are constantly popping up.

People are still improving CRISPR methods, Dr. Li said. Its quite an active area of research and development. Im sure that CRISPR will have even broader applications in the future.

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How CRISPR Is Changing Cancer Research and Treatment

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A new gene therapy can reverse the effects of heart failure and restore heart function in a large animal model.

The therapy increases the amount of blood the heart can pump and dramatically improves survival, in what a paper describing the results calls an unprecedented recovery of cardiac function.

Currently, heart failure is irreversible. In the absence of a heart transplant, most medical treatments aim to reduce the stress on the heart and slow the progression of the often-deadly disease.

But if the gene therapy shows similar results in future clinical trials, it could help heal the hearts of the 1 in 4 people alive today who will eventually develop heart failure.

The results appear in npj Regenerative Medicine.

The researchers were focused on restoring a critical heart protein called cardiac bridging integrator 1 (cBIN1). They knew that the level of cBIN1 was lower in heart failure patientsand that, the lower it was, the greater the risk of severe disease.

When cBIN1 is down, we know patients are not going to do well, says Robin Shaw, director of the Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI) at the University of Utah and a co-senior author on the study. It doesnt take a rocket scientist to say, What happens when we give it back?'

To try and increase cBIN1 levels in cases of heart failure, the researchers turned to a harmless virus commonly used in gene therapy to deliver an extra copy of the cBIN1 gene to heart cells. They injected the virus into the bloodstream of pigs with heart failure. The virus moved through the bloodstream into the heart, where it delivered the cBIN1 gene into heart cells.

For this heart failure model, heart failure generally leads to death within a few months. But all four pigs that received the gene therapy in their heart cells survived for six months, the endpoint of the study.

Importantly, the treatment didnt just prevent heart failure from worsening. Some key measures of heart function actually improved, suggesting the damaged heart was repairing itself.

Shaw emphasizes that this kind of reversal of existing damage is highly unusual.

In the history of heart failure research, we have not seen efficacy like this, Shaw says. Previous attempted therapies for heart failure have shown improvements to heart function on the order of 5-10%. cBIN1 gene therapy improved function by 30%. Its night and day, Shaw adds.

The treated hearts efficiency at pumping blood, which is the main measure of the severity of heart failure, increased over timenot to fully healthy levels, but to close that of healthy hearts. The hearts also stayed less dilated and less thinned out, closer in appearance to that of non-failing hearts.

Despite the fact that, throughout the trial, the gene-transferred animals experienced the same level of cardiovascular stress that had led to their heart failure, the treatment restored the amount of blood pumped per heartbeat back to entirely normal levels.

Even though the animals are still facing stress on the heart to induce heart failure, in animals that got the treatment, we saw recovery of heart function and that the heart also stabilizes or shrinks, says TingTing Hong, associate professor of pharmacology and toxicology and CVRTI investigator at the University of Utah and co-senior author on the study. We call this reverse remodeling. Its going back to what the normal heart should look like.

The researchers think that cBIN1s ability to rescue heart function hinges on its position as a scaffold that interacts with many of the other proteins important to the function of heart muscle.

cBIN1 serves as a centralized signaling hub, which actually regulates multiple downstream proteins, says Jing Li, associate instructor at CVRTI and first author on the study. By organizing the rest of the heart cell, cBIN1 helps restore critical functions of heart cells.

cBIN1 is bringing benefits to multiple signaling pathways, Li adds.

Indeed, the gene therapy seemed to improve heart function on the microscopic level, with better-organized heart cells and proteins. The researchers hope that cBIN1s role as a master regulator of heart cell architecture could help cBIN1 gene therapy succeed and introduce a new paradigm of heart failure treatment that targets heart muscle itself.

Along with industry partner TikkunLev Therapeutics, the team is currently adapting the gene therapy for use in humans and intend to apply for FDA approval for human clinical trial in fall of 2025. While the researchers are excited about the results so far, the therapy still has to pass toxicology testing and other safeguards. And, like many gene therapies, it remains to be seen if it will work for people who have picked up a natural immunity to the virus that carries the therapy.

But the researchers are optimistic. When you see large animal data thats really close to human physiology, it makes you think, Hong says. This human disease, which affects more than six million Americansmaybe this is something we can cure.

Funding for this study came from the National Institutes of Health and the Nora Eccles Treadwell Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest statement: The University of Utah has submitted a provisional patent application: Methods for rehabilitating heart failure using gene therapy (US 63/088, 123, Hong and Shaw), which has been licensed by TikkunLev Therapeutics Inc. Hong and Shaw received a Sponsored Research Award and stock options from TikkunLev Therapeutics Inc. Stavros Drakos, also an author on the study, is a consultant for Abbott and has received research support from Novartis.

Source: University of Utah

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Can a new gene therapy reverse heart failure? - Futurity