Special focus section: gene therapy for Parkinson's disease.

Over the past decade, in vivo gene replacement therapy has significantly advanced, resulting in market approval of numerous therapeutics predominantly relying on adeno-associated viral vectors (AAV). While viral vectors have undeniably addressed several critical healthcare challenges, their clinical application has unveiled a range of limitations and safety concerns. This review highlights the emerging challenges in the field of gene therapy. At first, we discuss both the role of biological barriers in viral gene therapy with a focus on AAVs, and review current landscape of in vivo human gene therapy. We delineate advantages and disadvantages of AAVs as gene delivery vehicles, mostly from the safety perspective (hepatotoxicity, cardiotoxicity, neurotoxicity, inflammatory responses etc.), and outline the mechanisms of adverse events in response to AAV. Contribution of every aspect of AAV vectors (genomic structure, capsid proteins) and host responses to injected AAV is considered and substantiated by basic, translational and clinical studies. The updated evaluation of recent AAV clinical trials and current medical experience clearly shows the risks of AAVs that sometimes overshadow the hopes for curing a hereditary disease. At last, a set of established and new molecular and nanotechnology tools and approaches are provided as potential solutions for mitigating or eliminating side effects. The increasing number of severe adverse reactions and, sadly deaths, demands decisive actions to resolve the issue of immune responses and extremely high doses of viral vectors used for gene therapy. In response to these challenges, various strategies are under development, including approaches aimed at augmenting characteristics of viral vectors and others focused on creating secure and efficacious non-viral vectors. This comprehensive review offers an overarching perspective on the present state of gene therapy utilizing both viral and non-viral vectors.

The menace of severe adverse events and deaths associated with viral gene therapy and its potential solution.

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. Regulatory T cells (Treg) are crucial for maintaining tolerance against self- or non-self- antigens. Importantly, Tregs also play an important role in dampening immune responses to AAV gene therapy, including tolerance induction to the transgene product. Approaches to harness the tolerogenic effect of Tregs include the use of selective IS drugs that expand existing Tregs, and skew activated conventional T cells into antigen specific peripherally induced Tregs. In addition, Tregs can be expanded ex vivo and delivered as cellular therapy. Further, receptor engineering can be used to increase the potency and specificity of Tregs allowing for suppression at lower doses and reducing the risk of disrupting protective immunity. Because immune mediated toxicities to AAV vectors are a concern in the clinic, strategies that can enhance or preserve Treg function should be considered to improve both the safety and efficacy of AAV gene therapy.  .

Role of FoxP3+ regulatory T cells in modulating immune responses to AAV gene therapy.

Adeno-associated virus (AAV) mediated gene therapy is a leading gene delivery platform with potential to transform the landscape of treatment for neurological disorders. While AAV is deemed non-immunogenic compared to other viral vectors, adverse immune reactions have been observed in the clinic, raising concerns. As the central nervous system (CNS) has a tightly regulated immune system, characterized by a degree of tolerance, it has been considered a unique target for AAV gene therapy. AAV vectors have shown promising results for the treatment of several CNS disorders including Spinal Muscular Atrophy, Giant Axonal Neuropathy, Amyotrophic Lateral Sclerosis, Tay Sachs Disease, Parkinson's Disease, and others, demonstrating safety and success. The Food and Drug Administration (FDA) approval of Zolgensma and European Medicines Agency (EMA) approval of Upstaza, for Spinal Muscular Atrophy (SMA) and Aromatic l-amino acid decarboxylase deficiency (AADC) respectively, represent this success, all while highlighting significant differences in immune responses to AAV, particularly with regards to therapeutic administration route. AAV therapies like Upstaza that are injected directly into the immune-specialized brain have been characterized by mild immune response profiles and minor adverse events, whereas therapies like Zolgensma that are injected systemically demonstrate more robust immune stimulation and off-target toxicities. Despite these contrasting parallels, these therapeutics and others in the clinic have demonstrated clinical benefit for patients, warranting further exploration of immune responses to CNS-directed AAV clinical trials. Thus, in this review, we discuss effects of different routes of AAV administration on eliciting local and peripheral immune responses specifically observed in CNS-targeted trials. 

Immune responses to central nervous system directed adeno-associated virus gene therapy: Does direct CNS delivery make a difference?

Abstract Introduction Valoctocogene roxaparvovec is an adeno‐associated virus vector serotype 5 (AAV5)‐mediated gene therapy approved for severe haemophilia A (HA). Aim To report the safety and efficacy of valoctocogene roxaparvovec 7 years after dosing in a phase 1/2 clinical study (NCT02576795). Methods Males ≥18 years with severe HA (factor VIII [FVIII] ≤1 international unit [IU]/dL) who were previously receiving exogenous FVIII and had no history of FVIII inhibitors or anti‐AAV5 antibodies received valoctocogene roxaparvovec treatment and were followed for 7 (6 × 10 13 vg/kg; n = 7) and 6 (4 × 10 13 vg/kg; n = 6) years. Results In the last year, one participant in each cohort reported treatment‐related adverse events (AEs): grade 1 (G1) hepatomegaly (6 × 10 13 ), and G1 splenomegaly and G1 hepatic steatosis (4 × 10 13 ). During all follow‐up, mean annualized treated bleeds and exogenous FVIII infusion rates were ≥88% lower than baseline values. At years 7 and 6, mean (median) FVIII activity (chromogenic assay) was 16.2 (10.3) and 6.7 (7.2) IU/dL in the 6 × 10 13 ( n = 5) and 4 × 10 13 ( n = 4) cohorts, respectively, corresponding to mild haemophilia. Regression analyses of the last year estimated rate of change in FVIII activity was ‐0.001 and ‐0.07 IU/dL/week for the 6 × 10 13 and 4 × 10 13 cohorts, respectively. Two participants (6 × 10 13 ) resumed prophylaxis in year 7: one after a non‐treatment‐related G4 serious AE of spontaneous internal carotid artery bleed, and the other to manage bleeds and FVIII activity. Conclusions The safety and efficacy of valoctocogene roxaparvovec remain generally consistent with previous reports, with good haemostatic control for most participants. Two participants returned to prophylaxis. 

Valoctocogene roxaparvovec gene therapy provides durable haemostatic control for up to 7 years for haemophilia A

The number of approved or investigational late phase viral vector gene therapies (GTx) has been rapidly growing. The adeno-associated virus vector (AAV) technology continues to be the most used GTx platform of choice. The presence of pre-existing anti-AAV immunity has been firmly established and is broadly viewed as a potential deterrent for successful AAV transduction with a possibility of negative impact on clinical efficacy and a connection to adverse events. Recommendations for the evaluation of humoral, including neutralizing and total antibody based, anti-AAV immune response have been presented elsewhere. This manuscript aims to cover considerations related to the assessment of anti-AAV cellular immune response, including review of correlations between humoral and cellular responses, potential value of cellular immunogenicity assessment, and commonly used analytical methodologies and parameters critical for monitoring assay performance. This manuscript was authored by a group of scientists involved in GTx development who represent several pharma and contract research organizations. It is our intent to provide recommendations and guidance to the industry sponsors, academic laboratories, and regulatory agencies working on AAV-based GTx viral vector modalities with the goal of achieving a more consistent approach to anti-AAV cellular immune response assessment.

/pdf/evaluation-of-cellular-immune-response-to-adeno-associated-3cmhoj4k.pdf

Evaluation of Cellular Immune Response to Adeno-Associated Virus-Based Gene Therapy

A regulatory perspective on the development of gene therapy for Parkinson's disease.

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Evaluation of Cellular Immune Response to Adeno-Associated Virus-Based Gene Therapy

A regulatory perspective on the development of gene therapy for Parkinson's disease.