Gene therapy for lipoprotein lipase deficiency: Working toward clinical application

Lipoprotein lipase (LPL) deficiency causes hypertriglyceridemia and recurrent, potentially life- threatening pancreatitis. There currently is no adequate treatment for this disease. Previously, we showed that intramuscular administration of an adeno- associated virus serotype 1 (AAV1) vector encoding the human LPLS447X variant cDNA (AAV1-LPLS447X) normalized the dyslipidemia of LPL-/- mice for more than 1 year. In preparation for a clinical trial, we evaluated the safety and biodistribution of AAV1-LPLS447X in wild- type mice and fully characterized six LPL-deficient patients. Toxicological analysis in mice showed that intramuscular administration was well tolerated. Acute inflammatory response markers were transiently increased, and anti-AAV1 antibodies were generated. Histological analyses indicated a dose- dependent reversible spleen hyperplasia, and myositis at the injection sites. Biodistribution data showed short- term vector leakage from injection sites into the circulation, followed by liver- mediated clearance. Persistence of vector DNA was limited to the injected muscle and draining lymph nodes, and spread to reproductive organs was limited. Characterization of LPL- deficient patients showed that all patients presented with hypertriglyceridemia and recurrent pancreatitis. LPL catalytic activity was absent, but LPL protein levels were 20 - 100% of normal. Myoblasts derived from skeletal muscle biopsies of these patients were efficiently transduced by AAV1- LPLS447X and secreted active LPL. These data support the initiation of a clinical trial in LPL- deficient patients, for which regulatory approval has been granted.