Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial

High AAV vector purity results in serotype- and tissue-independent enhancement of transduction efficiency

“…11,12 In contrast, in clinical studies in which smaller amounts of AAV vectors were introduced into immunoprivileged body compartments, limited or no immune responses to the AAV capsid were observed. [13][14][15][16] These data support that the route of administration and the total antigen load (that is total vector capsid dose) determine the kinetics and the nature of the immune response against the AAV capsid. Increasing the transgene expression efficiency, vector transduction efficiency, and vector purity, with the objective to minimize viral antigen dose and minimize potentially antigenic moieties, are important approaches to reduce the potential for deleterious host immune responses after vector administration.…”

“…20,22 Increasing vector purity and potency is predicted to reduce the risk of deleterious, efficacy-limiting immune responses after administration of recombinant AAV to human subjects, a critical consideration for an inherently immunogenic (that is viral) biologic product that will depend on avoidance of certain immune responses to achieve long-term efficacy. Studies in humans showed that, though low doses of highly purified vector administered to immunoprivileged sites (for example, eye, brain) result in minimal, non-efficacy-limiting immune responses, 15,16 larger doses of vector administered systemically in hemophilia B subjects 9 resulted in a capsid-specific CD8+ T-cell response that limited F.IX transgene expression. 10 Achieving higher vector purity is predicted to lower immunogenicity of the vector in animal models and humans by reducing the adjuvant effect of potentially immunostimulatory moieties such as residual non-self proteins (for example, excess viral capsids and other non-human proteins) and nucleic acids (for example, CpGs containing plasmid backbone sequences).…”

AAV for pain: steps towards clinical translation

“…17 Antibodies are often 'neutralizing', that is, counteracting the ability of rAAV to infect target cells. Serological immunity can also be induced, if rAAV is administered into the CNS of animals 34 or humans, [35][36][37] albeit the response seems to be milder and shorter lived. Whether systemic antibodies can interfere with transduction in the CNS and whether antibodies can be induced in the cerebrospinal fluid (CSF) will be discussed below in the sub-section Immunity in the CNS.…”

“…(Also, the retina lies adjacent to a confined fluid-filled space, presenting similarity to the DRG-directed IT gene therapy considered in this review.) The CNS disorders addressed in these trials were Canavan disease, 49 Parkinson's disease, 35,36,50 and Batten disease. 37 The retina-directed trials were for Leber's congenital amaurosis (LCA).…”

“…In LCA trials addressing this question, 51,52,54 no cellular immune response to the AAV capsid was detected. In two of the Parkinson's disease trials, evidence for persistence of transgene expression for more than 1 year was obtained by functional imaging, 35,36 further suggesting that no relevant cytotoxic immunity was mounted and that longterm gene expression in humans resembled the findings in laboratory models.…”