Abstract
Gene therapies are currently one of the most investigated therapeutic modalities in both the preclinical and clinical settings and have shown promise in treating a diverse spectrum of diseases. Gene therapies aim at introducing a gene material in target cells and represent a promising approach to cure diseases that were thought to be incurable by conventional modalities. In many cases, a gene therapy requires a vector to deliver gene therapeutics into target cells; viral vectors are among the most widely studied vectors owing to their distinguished advantages such as outstanding transduction efficiency. With decades of development, viral vector‐based gene therapies have achieved promising clinical outcomes with many products approved for treating a range of diseases including cancer, infectious diseases and monogenic diseases. In addition, a number of active clinical trials are underway to further expand their therapeutic potential. In this review, we highlight the diversity of viral vectors, review approved products, and discuss the current clinical landscape of in vivo viral vector‐based gene therapies. We have reviewed 13 approved products and their clinical applications. We have also analyzed more than 200 active trials based on various viral vectors and discussed their respective therapeutic applications. Moreover, we provide a critical analysis of the major translational challenges for in vivo viral vector‐based gene therapies and discuss possible strategies to address the same.
Highlights
Gene therapy, modifying expression of genes or correcting dysfunctional genes, offers great potential as a therapeutic modality for treating a plethora of diseases.[1,2,3] Unlike traditional drugs, gene therapy genetically modifies cells and opens possibilities of curing diseases that were once thought to be incurable.[4,5] The concept of gene therapy can date back to the 1960s when early studies demonstrated that DNA sequences could be introduced into mammalian cells for gene repair.[6]
Decades of scientific efforts led to the first human gene therapy clinical trial in 1990 using a retrovirus vector technology for treating severe combined immunodeficiency.[7,8]
Gene therapy experienced a major setback in late 1990s following the death of a patient due to immune responses caused by the viral vector in a trial in 1999 and the development of viral vectorinduced leukemia in four patients after receiving a retrovirus-based gene therapy in another trial in 2000.9 These two events brought gene therapy to a temporary halt in the clinic, raised concerns about its safety, and highlighted the critical need for safer viral vectors
Summary
Gene therapy, modifying expression of genes or correcting dysfunctional genes, offers great potential as a therapeutic modality for treating a plethora of diseases.[1,2,3] Unlike traditional drugs, gene therapy genetically modifies cells and opens possibilities of curing diseases that were once thought to be incurable.[4,5] The concept of gene therapy can date back to the 1960s when early studies demonstrated that DNA sequences could be introduced into mammalian cells for gene repair.[6]. AAV is a nonpathogenic parvovirus with a 4.7 kb DNA genome enclosed in a nonenveloped icosahedral capsid.[37] AAV has 11 natural serotypes and over 100 variants.[38,39] Different serotypes have tropism toward different tissues that makes each serotype suitable for gene delivery to specific tissues.[40] For example, AAV9 exhibits tropism toward central nervous system (CNS) organs while AAV8 can effectively transduce pancreas.[18,41] Major characteristics of AAV vectors include: (1) they can transduce both diving and nondiving cells and do not integrate DNA into host genome; (2) they can enable long-term, stable gene expression; (3) they have low immunogenicity Due to these unique features, AAV is the most suitable viral vector for in vivo gene therapies, especially for conditions that require long-term gene modifications.[42] Their primary clinical applications cover the treatment of a broad array of monogenic diseases including ophthalmological diseases, metabolic diseases, hematological diseases, neurological diseases, and musculoskeletal diseases.[43].
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