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 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.
Rip
Jaap
J
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Nierman
Melchior C
MC
Sierts
Jeroen A
JA
Petersen
Wilma
W
Van den Oever
Karin
K
Van Raalte
Daniel
D
Ross
Colin J D
CJ
Hayden
Michael R
MR
Bakker
Andrew C
AC
Dijkhuizen
Paul
P
Hermens
Wim T
WT
Twisk
Jaap
J
Stroes
Erik
E
Kastelein
John J P
JJ
Kuivenhoven
Jan Albert
JA
Meulenberg
Janneke M
JM
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D005240:Feasibility Studies; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors; D008072:Hyperlipoproteinemia Type I / Q000628:therapy*; D007273:Injections, Intramuscular; D008071:Lipoprotein Lipase / Q000008:administration & dosage / Q000235:genetics* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014018:Tissue Distribution
D008071:Lipoprotein Lipase