Apolipoprotein E hepatic control region/human alpha-1-antitrypsin composite promoter (LP1)
Compact chimeric liver promoter, known as LP1, combining a core fragment of the human apolipoprotein E (ApoE) hepatic control region with the human alpha-1-antitrypsin (hAAT) gene promoter. Drives high-level, hepatocyte-restricted transgene expression and is the liver-specific promoter used in the AAV8 vector for the first successful hemophilia B gene therapy trial.
Characteristics
Combines a 309 bp core fragment of the human ApoE hepatic control region with a 255 bp fragment of the human alpha-1-antitrypsin promoter upstream of a modified SV40 intron, compacted to fit self-complementary AAV packaging limits (Nathwani et al. 2006). In mice given 1e11 vg of scAAV2/8-LP1-hFIX, LP1 drives expression in 25% of hepatocytes by day 7, rising to over 90% by 6 weeks, and produces roughly 20-fold higher factor IX levels than single-stranded AAV at an equivalent dose; in non-human primates, 1e12 vg/kg achieves 12-30% of normal factor IX levels (Nathwani et al. 2006).
Applications: Drives liver-restricted transgene expression in self-complementary AAV8 vectors for hemophilia B gene therapy; used in the first clinical trial of AAV-mediated factor IX gene transfer (scAAV2/8-LP1-hFIXco), which raised factor IX activity to 2-11% of normal in patients with severe hemophilia B (Nathwani et al. 2011).
Limitations: Restricted to hepatocytes and not suited for extrahepatic targeting. High-dose AAV8-LP1 vector delivery has triggered transient, immune-mediated elevation of liver transaminases in gene therapy patients, sometimes requiring a short course of glucocorticoids to preserve transgene expression (Nathwani et al. 2011).
References
- Nathwani et al. (2011). Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med - Nathwani 2011 Hemophilia B