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Duchenne muscular dystrophy (DMD) has been a major target for gene therapy development for nearly 30 years. DMD is among the most common genetic diseases, and isolation of the defective gene (DMD, or dystrophin) was a landmark discovery, as it was the first time a human disease gene had been cloned without knowledge of the protein product. Despite tremendous obstacles, including the enormous size of the gene and the large volume of muscle tissue in the human body, efforts to devise a treatment based on gene replacement have advanced steadily through the combined efforts of dozens of labs and patient advocacy groups. Progress in the development of DMD gene therapy has been well documented in Molecular Therapy over the past 20 years and will be reviewed here to highlight prospects for success in the imminent human clinical trials planned by several groups. Duchenne muscular dystrophy (DMD) is one of the most common human genetic disorders. Cloning of the DMD gene preceded the human genome project and established DMD as an early gene therapy target. We summarize progress using AAV vectors for bodywide dystrophin gene delivery, an approach rapidly moving into clinical trials.

Hundreds of scientists had worked on mRNA vaccines for decades before the coronavirus pandemic brought a breakthrough. Hundreds of scientists had worked on mRNA vaccines for decades before the coronavirus pandemic brought a breakthrough.

Cardiovascular diseases remain a large global health problem. Although several conventional small-molecule treatments are available for common cardiovascular problems, gene therapy is a potential treatment option for acquired and inherited cardiovascular diseases that remain with unmet clinical needs. Among potential targets for gene therapy are severe cardiac and peripheral ischemia, heart failure, vein graft failure, and some forms of dyslipidemias. The first approved gene therapy in the Western world was indicated for lipoprotein lipase deficiency, which causes high plasma triglyceride levels. With improved gene delivery methods and more efficient vectors, together with interventional transgene strategies aligned for a better understanding of the pathophysiology of these diseases, new approaches are currently tested for safety and efficacy in clinical trials. In this article, we integrate a historical perspective with recent advances that will likely affect clinical development in this research area. Ylä-Herttuala and Baker summarize recent advances and the current status of cardiovascular gene therapy with special emphasis on new clinical initiatives and lessons learned from previous clinical trials, including a discussion of the selection of patient populations, endpoints, and best available treatment strategies.

As gene therapy continues to change, so must the federal framework set up to oversee it. As new biotechnologies continue to emerge, the NIH and the FDA are proposing reductions in duplicative oversight and changes to the role of the Recombinant DNA Advisory Committee.

The concept of gene therapy originated in the mid twentieth century and was perceived as a revolutionary technology with the promise to cure almost any disease of which the molecular basis was understood. Since then, several gene vectors have been developed and the feasibility of gene therapy has been shown in many animal models of human disease. However, clinical efficacy could not be demonstrated until the beginning of the new century in a small-scale clinical trial curing an otherwise fatal immunodeficiency disorder in children. This first success, achieved after retroviral therapy, was later overshadowed by the occurrence of vector-related leukemia in a significant number of the treated children, demonstrating that the future success of gene therapy depends on our understanding of vector biology. This has led to the development of later-generation vectors with improved efficiency, specificity, and safety. Amongst these are HIV-1 lentivirus-based vectors (lentivectors), which are being increasingly used in basic and applied research. Human gene therapy clinical trials are currently underway using lentivectors in a wide range of human diseases. The intention of this review is to describe the main scientific steps leading to the engineering of HIV-1 lentiviral vectors and place them in the context of current human gene therapy.

Gene therapy is a promising molecular approach for the management of familial hearing loss. This type of molecular therapy is the physical manifestation of genetic determinism—the notion that individual genes cause individual phenotypes. The current composition weaves through various branches of the biomedical sciences to uncover the molecular biologic premise for genetic determinism and the impetus behind gene therapy. Consequently, it is revealed that the underlying molecular biologic premise was scaffolded on successful observations from simple biologic assays that were devoid of the complexities of human disease biology. Furthermore, modern successful gene therapies are largely driven by commercial and academic incentives at the cost of scientific rigor. This poses several perverse challenges for patients, clinicians and the public at large. Issues concerning safety, efficacy, and ethics are far from resolved despite regulatory agency approvals, the media’s bias for gene therapy and the many lucrative investor positions. Lastly, the therapeutic claims regarding gene therapy are the most ambitious claims made within the hearing sciences. Therefore, scientists, clinicians, and patients must be equipped with the tools needed to appropriately consume and appraise such claims. These and other issues are also directly addressed, with the aim of providing a realistic sense of whether current human gene therapies are ready to be positioned within our routine clinical armamentarium against hearing loss.

The first medical interventions were often individualized but ineffective, because doctors lacked an understanding of disease biology. As medicine became more scientific, physicians started grouping patients by disease. Now, genetic insights let doctors consider their patients' unique make-up when prescribing treatments.

Prior to the first successful bone marrow transplant in 1968, patients born with severe combined immunodeficiency (SCID) invariably died. Today, with a widening availability of newborn screening, major improvements in the application of allogeneic procedures, and the emergence of successful hematopoietic stem and progenitor cell (HSC/P) gene therapy, the majority of these children can be identified and cured. Here, we trace key steps in the development of clinical gene therapy for SCID and other primary immunodeficiencies (PIDs), and review the prospects for adoption of new targets and technologies.

From its earliest conception, gene therapy held the promise of correcting inherited diseases by inserting a normal copy of the relevant gene into somatic cells. 1 Common monogenic diseases of blood cells, such as sickle cell disease or β-thalassemia, were originally considered important candidates for gene therapy because they were well understood at the molecular level and because the target cell, the hematopoietic stem cell, is easily accessible and can be explanted, genetically corrected in the laboratory, and then retransplanted. 2 The advantage of gene therapy over the conventional transplantation of hematopoietic stem cells from compatible donors is that gene therapy is . . .