Abstract
Lipoprotein lipase (LPL) deficiency cannot be effectively treated and causes severe hypertriglyceridemia and pancreatitis. We have reported that adeno-associated virus serotype 1 (AAV1) based gene therapy normalizes triglyceride levels in LPL deficient mice and cats. The current study evaluates safety and biodistribution of the same vector, AAV1-LPLS447X, and addresses clinical application. Toxicological analysis after intramuscular administration of AAV1-LPLS447X (1E11-1E13 gc/kg) in murine dose-escalation studies did not reveal clinical or hematological changes. Shortly after administration (7 days), vector DNA was found in injected muscle, draining lymph nodes, and filtering organs while spread to reproductive organs was limited. 28 and 90 days post injection, vector DNA levels dissipated in all tissues except for injected muscle and lymph nodes. Furthermore, we studied 6 LPL deficient patients to assess eligibility for a first clinical trial. All presented with absence of LPL catalytic activity but LPL protein levels were 19-103% of normal. Infection of patient's myoblasts with AAV1-LPLS447X resulted in the secretion of catalytically active LPL in all cases. The efficacy and safety data obtained so far support the initiation of a clinical trial to test this vector in LPL deficient patients.
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