Phase 2 Clinical Trial of a Recombinant Adeno-Associated Viral Vector Expressing α 1 -Antitrypsin: Interim Results

University of Massachusetts Medical School, 55 Lake Avenue North,Worcester, MA 01655, USA.
Human gene therapy (Impact Factor: 3.76). 05/2011; 22(10):1239-47. DOI: 10.1089/hum.2011.053
Source: PubMed


Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α(1)-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×10(11), 1.9×10(12), and 6.0×10(12) vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with only mild injection site reactions and no serious adverse events. Serum creatine kinase was transiently elevated on day 30 in five of six subjects in the two higher dose groups and normalized by day 45. As expected, all subjects developed anti-AAV antibodies and interferon-γ enzyme-linked immunospot responses to AAV peptides, and no subjects developed antibodies to AAT. One subject in the mid-dose group developed T cell responses to a single AAT peptide unassociated with any clinical effects. Muscle biopsies obtained on day 90 showed strong immunostaining for AAT and moderate to marked inflammatory cell infiltrates composed primarily of CD3-reactive T lymphocytes that were primarily of the CD8(+) subtype. These results support the feasibility and safety of AAV gene therapy for AAT deficiency, and indicate that serum levels of vector-derived normal human AAT >20 μg/ml can be achieved. However, further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations.

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    • "Adeno-associated virus vector-induced T cell immunity is not unique to liver-directed gene transfer. Monitoring of capsid T cell responses has been performed in the context of several muscle-directed gene transfer clinical studies (41, 85–92) as well. In agreement with the findings in AAV liver gene transfer studies, results accumulated for muscle gene transfer suggest that the magnitude of T cell responses directed against the AAV capsid correlates with the dose of vector administered (65, 92). "
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    Frontiers in Immunology 07/2014; 5:350. DOI:10.3389/fimmu.2014.00350
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    • "No humoral or cellular immune responses to the LPL transgene were observed (Gaudet et al., 2013). Cellular immune responses were also noted in other clinical studies in which rAAV vectors were administered locally, by IM injection (Brantly et al., 2009; Flotte et al., 2011). However, as with alipogene tiparvovec, these studies showed sustained transgene expression (a1-antitrypsin AAT) for at least 1 year after delivery, suggesting that in this case the cellular immune responses to the AAV capsid had not eliminated transgene expression (Brantly et al., 2009). "
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    • "Investigators using non-human primates and an AAV8 vector have shown minimal impact on systemic gene expression in the presence of AAV8 NAbs as high as 1/320 when monkeys were injected directly into muscle (61). A similar approach has been used in clinical trials for A1AT deficiency and hemophilia B using AAV1 and AAV2 vectors respectively, demonstrating that high titers of AAV NAb did not prevent gene transfer (15, 52, 62). The retina has also been used as a target organ for AAV-mediated gene therapy for localized systemic expression of therapeutic proteins such us erythropoietin (63). "
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