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: 3.62). 05/2011; 22(10):1239-47. DOI: 10.1089/hum.2011.053
Source: PubMed

ABSTRACT 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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Available from: Christian Mueller, Aug 01, 2015
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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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    • "In a clinical trial for alpha-1 antitrypsin (AAT) deficiency (Brantly et al., 2009), humoral (by day 14) and T cell (by day 14, responses to AAV1 capsid were observed in all subjects though these immune responses did not diminish the low level of transgene expression that was observed. A recent phase II clinical trial by Flotte et al. (2011) further confirmed moderate to marked CD8 + T cell responses against AAV1 capsid protein following delivery of AAV1–AAT to muscles of patients. AAT expression was sustained but declined after day 30, and serum therapeutic AAT level was not achieved in any of the patients receiving either 6 × 10 11 , 1.9 × 10 12 , or 6 × 10 12 vg/kg. "
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