Gene therapy for lipoprotein lipase deficiency: Working toward clinical application

Jaap Rip, Melchior C. Nierman, Jeroen A. Sierts, Wilma Petersen, Karin van den Oever, Daniel van Raalte, Colin J. D. Ross, Michael R. Hayden, Andrew C. Bakker, Paul Dijkhuizen, Wim T. Hermens, Jaap Twisk, Erik Stroes, John J. P. Kastelein, Jan Albert Kuivenhoven, Janneke M. Meulenberg

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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. © Mary Ann Liebert, Inc.
Original languageEnglish
Pages (from-to)1276-1286
JournalHuman gene therapy
Issue number11
Publication statusPublished - 2005

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