P.105INCEPTUS pre-phase 1, prospective, non-interventional, natural history run-in study to evaluate subjects aged 4 years and younger with X-linked myotubular myopathy (XLMTM)

Servais, Laurent; Shieh, Perry B.; Dowling, James J.; Kuntz, N.; Müller‐Felber, Wolfgang; Smith, B.J.; Bönnemann, C.; Muntoni, Francesco; Bilder, Deborah A.; Duong, Tina; Graham, Robert J.; Jain, Mohit; Lawlor, Michael W.; MacBean, Victoria; Noursalehi, Mojtaba; Pitts, Teresa; Rafferty, GF; Rico, Salvador; Prasad, Sanjay

doi:10.1016/j.nmd.2019.06.161

Cited by 1 publication

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“…Similarly, in a trial for a-1 antitrypsin (AAT) deficiency, following intramuscular delivery of an AAV vector, cytolytic T cells were detected in association with decreased transgene expression in one of the participants, 86 although the trial showed overall long-term expression of the transgene in most participants. 4 More recently, in the context of systemic delivery of an AAV vector for the treatment of X-linked myotubular myopathy, anti-transgene antibodies were detected, 87 although with no direct correlation with clinical endpoints (vide infra). Finally, transgene-reactive T cells were also detected in a phase I/II trial of intracranial delivery of an AAV5 vector to the brain of children affected by mucopolysaccharidosis type IIIB.…”

Section: Immune Responses Against the Transgene Productmentioning

confidence: 99%

AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer

2020

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Gene therapy with adeno-associated virus (AAV) vectors has demonstrated safety and long-term efficacy in a number of trials across target organs, including eye, liver, skeletal muscle, and the central nervous system. Since the initial evidence that AAV vectors can elicit capsid T cell responses in humans, which can affect the duration of transgene expression, much progress has been made in understanding and modulating AAV vector immunogenicity. It is now well established that exposure to wild-type AAV results in priming of the immune system against the virus, with development of both humoral and T cell immunity. Aside from the neutralizing effect of antibodies, the impact of pre-existing immunity to AAV on gene transfer is still poorly understood. Herein, we review data emerging from clinical trials across a broad range of gene therapy applications. Common features of immune responses to AAV can be found, suggesting, for example, that vector immunogenicity is dose-dependent, and that innate immunity plays an important role in the outcome of gene transfer. A range of host-specific factors are also likely to be important, and a comprehensive understanding of the mechanisms driving AAV vector immunogenicity in humans will be key to unlocking the full potential of in vivo gene therapy. Pre-existing Immunity to WT AAV in Humans Pre-existing Humoral ImmunitySeveral studies have investigated the seroprevalence of neutralizing antibodies directed against WT AAV in humans. [20][21][22][23][24][25] Seroprevalence varies geographically, with anti-AAV2 neutralizing antibodies displaying the highest prevalence, ranging from 30% to 60% of the population. Due to the broad cross-reactivity between AAV serotypes, 26 neutralizing antibodies recognizing virtually all serotypes can be found in almost all subjects. 27 This cross-reactivity reflects the amino acid sequence and structural homology across capsids of different AAV serotypes. 28 The prevalence of total anti-AAV antibodies is close to 70% of the population for AAV1 and AAV2, 45% for AAV6 and AAV9, and 38% for AAV8. 20 Importantly, titers of anti-AAV immunoglobulin G (IgG) antibodies correlate significantly with titers of

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Section: Immune Responses Against the Transgene Productmentioning

confidence: 99%