40. Correction of Dyslipidemia in Murine and Feline Models of Lipoprotein Lipase Deficiency by Intramuscular Administration of AAV1-LPLS447X

Abstract

Lipoprotein lipase (LPL) deficiency is characterized by excessive plasma triglyceride levels (TG), resulting in visibly milky plasma and severe clinical symptoms including life-threatening pancreatitis. There is no treatment for this inherited metabolic disease. We therefore proposed to test LPL gene therapy, expressing the human LPL variant S447X in muscle. This naturally-occurring variant is associated with a beneficial lipid profile in man, and improved disease correction over wild type LPL following adenoviral transfer to LPL deficient (LPL−/−) mice. To realize long-term correction of hypertriglyceridemia, adeno-associated virus serotype 1 (AAV1) was used to instill stable expression of LPLS447X in muscle. IM administration of 8×1011–8×1012 gc/kg AAV1-LPLS447X in LPL−/− mice was sufficient to reduce plasma TG levels (by up to 98%, from 99 to 1.8 mmol/L). These beneficial effects were observed within 1 week post-transfer, and lasted for >1 year. Importantly, only a fraction of LPL activity ( 98% reduction of plasma TG within 1 week. After 3 weeks, antibodies against human LPL were detected in plasma, and TG levels returned to pre-treatment levels. In accordance, LPL expression was greatly reduced. In contrast to LPL−/− mice that have low residual levels of LPL activity and protein, LPL−/− cats have no detectable LPL protein mass. Therefore, administration of LPLS447X to LPL−/− cats likely provoked an immune response that abrogated treatment efficacy. CONCLUSION: AAV1-mediated delivery of LPLS447X to muscle provides immediate correction of hypertriglyceridemia in two different animal models of LPL deficiency.