Clinical Considerations for Capsid Choice in the Development of Liver-Targeted AAV-Based Gene Transfer

Abstract

As gene transfer with adeno-associated virus (AAV) vectors is starting to enter clinical practice, this review examines the impact of vector capsid choice in liver-directed gene transfer for hemophilia. Given that there are multiple clinical trials completed and ongoing in this field, it is important to review the clinical evidence, particularly as a range of AAV-vector serotypes including AAV2, AAV5, AAV8, and AAV10 have been tested. Although there have been a number of successful trials, the development of two investigational AAV vectors for hemophilia B has been discontinued because they did not meet efficacy and/or safety expectations. Whether this difference between success and failure of gene transfer approaches reflects capsid choice, vector design, manufacturing system, or other variables is a question of great interest. Here, we examine the body of evidence across trials to determine the possible influences of serotype choice on key clinical outcomes such as safety, vector clearance, treatment eligibility, occurrence of transaminase elevations, activation of capsid-directed cytotoxic T cell responses, and clinical efficacy. In summary, gene transfer requires a balance between achieving sufficient transgene expression and minimizing destructive immune responses, which may be affected by AAV-vector serotype choice.

Adipose Tissue: An Emerging Target for Adeno-associated Viral Vectors

“…Currently there are 13 AAV serotypes identified and at least 11 serotypes commonly available in the laboratory setting. 9 Serotypes 1, 4, and 7–11 were discovered in non-human primates, while serotypes 2, 3, 5, and 6 were isolated from humans. 10 , 11 , 12 In addition to these mostly applied serotypes, there are more than 100 capsid variants that have been identified from human and nonhuman primates.…”

Protocol for In Vivo Evaluation and Use of Destabilizing Domains in the Eye, Liver, and Beyond

“…The mouse liver is a large and easily accessible organ through a tail vein injection. Hepatocytes are robustly transduced by a number of serotypes including AAV2/2, AAV5/5, AAV8/8 and AAV10/10 ( Pipe et al, 2019 ). We have specifically utilized the AAV2/8 serotype developed for even and strong transduction at a lower titer than the conventionally used AAV8/8 serotype, making it much more translatable to human disease in which viral dose must be kept as low as possible ( Cingolani et al, 2012 ).…”

Evolving AAV-delivered therapeutics towards ultimate cures

“…The research using hemophilia as a study model has pioneered liver-based gene therapy [ 22 , 25 ]. The promising results from optimizing different aspects of recombinant AAV for gene delivery, including vectors, capsids, route, dose, toxicity, and immunogenicity, have paved the way for developing gene therapy for many other liver-based inherited diseases which have led to a number of clinical trials to date [ 26 ]. These include the AAV-based treatments for alpha 1-antitrypsin (AAT) deficiency, phenylketonuria (PKU), ornithine transcarbamylase deficiency, Crigler-Najjar syndrome, homozygous familial hypercholesterolemia (FH), and glycogen storage disease type Ia (GSD1a) ( https://clinicaltrials.gov/ ) [ 27 , 28 ].…”

“…It is noteworthy that hemophilia is low-hanging fruit because a very low level of gene transfer and expression is sufficient to confer therapeutic benefits [ 22 , 25 ]. In many other diseases, much higher AAV doses are needed to convey therapeutic benefits from transgenes expression and have been reported to be associated with severe toxicity [ 15 , 16 , 26 ]. In a recent study, a clinical trial named “AT132” injected AAV8 at 1 × 10 14 and 3 × 10 14 vg/kg to treat X-linked myotubular myopathy (NCT03199469).…”

“…As a result, AAV-based gene delivery is rarely used to target fast-proliferating cells such as hematopoietic progenitors and stem cells. Evidences from multiple clinical studies on AAV-based gene therapy in adult patients with hemophilia B have also reported expression loss, despite a significant reduction in bleeding episodes [ 26 ]. Young children are seldom recruited in clinical trials for AAV-based gene therapy due to general safety concerns as well as vector dilution [ 10 , 21 ].…”