• Major finding: One dose of an AAV-based vector results in long-term expression of a FIX transgene.

  • Approach: A combined phase I/II clinical trial monitored safety and efficacy of transgene expression.

  • Impact: A virus-based delivery vector can express therapeutic levels of a circulating protein.

The field of gene therapy has expanded from treating diseases with a single genetic defect to include experimental treatments for cancer. Yet, several universal uncertainties accompany all gene therapy experiments, including delivery vector efficiency, short- and long-term safety, and response duration. In a combined phase I/II clinical trial, Nathwani and colleagues successfully used gene therapy to treat patients with hemophilia B, an X-linked bleeding disorder caused by loss of the coagulation protein factor IX (FIX). Three groups of 2 patients each were given a single peripheral infusion of increasing doses of scAAV2/8-LP1-hFIXco, a serotype 2–based adenovirus-associated virus (AAV2) vector. Unlike other previously tested AAV2-based gene therapy vectors, scAAV2/8-LP1-hFIXco includes a liver-specific promoter, a self-complementary codon-optimized human FIX cDNA that mediates higher levels of transgene expression than single-stranded AAV vectors, and an AAV serotype-8–pseudotyped capsid, which minimizes the host immune response. Significantly, all 6 patients responded to the therapy in a roughly dose-dependent manner, with increased endogenous expression of FIX that has remained stable for at least 6 months. One patient showed signs of immune-mediated clearance of AAV-transduced hepatocytes that was corrected with a short course of steroids, but none had an immunologic response to the transgene product itself. Although additional follow-up is required to confirm the ongoing safety and efficacy of scAAV2/8-LP1-hFIXco, these findings represent a major advance for the gene therapy field that one hopes will translate into novel gene-based therapeutics for additional disease classes.

Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011 Dec 10. [Epub ahead of print].

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