Human Gene Therapy

Recombinant adeno-associated virus (rAAV) vectors appear, more than ever, to be efficient viral vectors for in vivo gene transfer as illustrated by the approvals of 7 drugs across Europe and the USA. Nevertheless, pre-existing immunity to AAV capsid in humans remains one of the major limits for a successful clinical translation. Whereas pre-existing humoral response to AAV capsid is well documented, the prevalence of pre-existing capsid-specific T cell responses still needs to be studied and characterized. Here, we investigated the prevalence of AAV-specific circulating T cells towards AAV2, 4, 5, 8, 9 and rh10 in a large cohort of healthy donors using the standard IFNγ ELISpot assay...

Adeno-associated viral (AAV) vectors have emerged as crucial tools in advancing gene therapy for skeletal diseases, offering the potential for sustained expression with low post-infection immunogenicity and pathogenicity. Preclinical studies support both the therapeutic efficacy and safety of these vectors, illustrating the promise of AAV-mediated gene therapy. Emerging technologies and innovations in AAV-mediated gene therapy strategies, such as gene addition, gene replacement, gene silencing, and gene editing, offer new approaches to clinical application...

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Cell and gene therapy innovations have provided several significant breakthroughs in recent years. However, cell and gene therapies often come with a high upfront cost, raising questions about patient access, affordability, and long-term value. This study reviewed cost-effectiveness analysis studies that have attempted to assess the long-term value of FDA-approved cell and gene therapies. Two reviewers independently searched the Tufts Medical Center Cost-Effectiveness Analysis Registry to identify all studies for FDA-approved cell and gene therapies per January 2023...

Adeno-associated virus (AAV) gene therapy is making rapid strides due to its wide range of therapeutic applications. However, development of serious immune responses to the capsid antigen or the therapeutic transgene product hinders its full clinical impact. Immune suppressive (IS) drug treatments have been used in various clinical trials to prevent the deleterious effects of cytotoxic T cells to the viral vector or transgene, although there isn't a consensus on the best treatment regimen, dosage, or schedule...

Liver injury with concomitant loss of therapeutic transgene expression can be a clinical sequela of systemic administration of rAAV when used for gene therapy, and a significant barrier to treatment efficacy. Despite this, it has been difficult to replicate this phenotype in preclinical models, thereby limiting the field's ability to systematically investigate underlying biological mechanisms and develop interventions. Prior animal models have focused on capsid and transgene-related immunogenicity but the impact of concurrently present non-transgene or vector antigens on therapeutic efficacy, such as those derived from contaminating nucleic acids within rAAV preps, has yet to be investigated...

BACKGROUND: Oncolytic viruses (OVs) have emerged as promising agents for antitumor therapy; however, their effectiveness remains limited. Our objective in this study was to enhance the antitumor efficacy of OVs by combining them with immune checkpoint inhibitors (ICIs). METHODS: Using reverse genetics technology, we developed a novel oncolytic influenza virus called delNS1-GM-CSF. Characterization of delNS1-GM-CSF included hemagglutination and TCID50 assays, followed by purification and observation of viral morphology using electron microscopy...

Delivering vectorized information into cells with the help of viruses has been of high interest to fundamental and applied science, and bears significant therapeutic promise. Human adenoviruses (HAdVs) have been at the forefront of gene delivery for many years, and the subject of intensive development resulting in several generations of agents, including replication-competent, -defective or retargeted vectors, and recently also helper-dependent (HD), so-called gutless vectors lacking any viral protein coding information...

Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α-galactosidase A (α-Gal A), an enzyme that hydrolyzes glycosphingolipids in lysosome. Accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in tissues induces cellular dysfunction leading to multi-organ disorder. Gene therapy is a promising strategy that can overcome these problems, and virus vectors such as adeno-associated virus (AAV) have been used for study on gene therapy. We used human Gb3 synthetase-transgenic (TgG3S)/α-Gal A knockout (GLAko) mice...

Mutations in the Rhodopsin (RHO) gene are the predominant causes of autosomal dominant retinitis pigmentosa (adRP). Given the diverse gain-of-function mutations, therapeutic strategies targeting specific sequences face significant challenges. Here, we provide a universal approach to conquer this problem: we have devised a CRISPR-Cas12i-based, mutation-independent gene knockout and replacement compound therapy carried by a dual AAV8 system. In this study, we successfully delayed the progression of retinal degeneration in the classic mouse disease model Rho P23H , and also Rho P347S , a new native mouse mutation model we developed...

Inflammatory diseases are conditions characterized by abnormal and often excessive immune responses, leading to tissue and organ inflammation. The complexity of these disorders arises from the intricate interplay of genetic factors and immune responses, which challenges conventional therapeutic approaches. However, the field of genetic manipulation has sparked unprecedented optimism in addressing these complex disorders. This review aims to comprehensively explore the application of gene therapy and gene editing in the context of inflammatory diseases, offering solutions that range from correcting genetic defects to precise immune modulation...

Adeno-associated virus (AAV)-based gene therapies have shown promise as novel treatments for rare genetic disorders such as Haemophilia A and Spinal Muscular Atrophy. However, cellular immune responses mediated by cytotoxic (CD8+) and helper (CD4+) T cells may target vector-transduced cells as well as healthy immune cells, impacting safety and efficacy. Here, we describe the optimization and reproducibility of interferon-γ (IFNγ)- and interleukin-2 (IL-2)-based Enzyme-Linked Immunosorbent Spot (ELISpot) assays for measuring T cell responses against AAV peptide antigens...

Interleukin 7 Receptor  Severe Combined Immunodeficiency (IL7R-SCID) is a life-threatening disorder caused by homozygous mutations in the IL7RA gene. Defective IL7R expression in humans hampers T cell precursors proliferation and differentiation during lymphopoiesis resulting in absence of T cells in newborns, who succumb to severe infections and death early after birth. Previous attempts to tackle IL7R-SCID by viral gene therapy have shown that unregulated IL7R expression predisposes to leukaemia, suggesting the application of targeted gene editing to insert a correct copy of the IL7RA gene in its genomic locus and mediate its physiological expression as a more feasible therapeutic approach...

Adeno-associated virus (AAV) vectors represent a novel tool for the delivery of genetic therapeutics and enable the treatment of a wide range of diseases. Success of this new modality is challenged, however, by cases of immune-related toxicities that complicate the clinical management of patients and potentially limit the therapeutic efficacy of AAV gene therapy. While significant progress has been made to manage immune-related liver enzyme elevations following systemic AAV delivery in humans, recent clinical trials utilizing high vector doses have highlighted a new challenge to AAV gene transfer - activation of the complement system...

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Inherited kidney diseases are among the leading causes of chronic kidney disease, reducing the quality of life and resulting in substantial socioeconomic impact. The advent of early genetic testing and the growing understanding of the molecular basis and pathophysiology of these disorders have opened avenues for novel treatment strategies. Viral vector-based gene therapies have evolved from experimental treatments for rare diseases to potent platforms that carry the intrinsic potential to provide a cure with a single application...

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