Gene therapy for lipoprotein lipase deficiency: working toward clinical application

Hum Gene Ther. 2005 Nov;16(11):1276-86. doi: 10.1089/hum.2005.16.1276.


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 LPL(S447X) variant cDNA (AAV1-LPL(S447X)) 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-LPL(S447X) 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-LPL(S447X) and secreted active LPL. These data support the initiation of a clinical trial in LPL-deficient patients, for which regulatory approval has been granted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dependovirus / genetics
  • Feasibility Studies
  • Female
  • Genetic Therapy* / adverse effects
  • Genetic Vectors
  • Hyperlipoproteinemia Type I / therapy*
  • Injections, Intramuscular
  • Lipoprotein Lipase / administration & dosage
  • Lipoprotein Lipase / genetics*
  • Lipoprotein Lipase / pharmacokinetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Tissue Distribution


  • Lipoprotein Lipase