TY - JOUR
T1 - Gene therapy for lipoprotein lipase deficiency: Working toward clinical application
AU - Rip, Jaap
AU - Nierman, Melchior C.
AU - Sierts, Jeroen A.
AU - Petersen, Wilma
AU - van den Oever, Karin
AU - van Raalte, Daniel
AU - Ross, Colin J. D.
AU - Hayden, Michael R.
AU - Bakker, Andrew C.
AU - Dijkhuizen, Paul
AU - Hermens, Wim T.
AU - Twisk, Jaap
AU - Stroes, Erik
AU - Kastelein, John J. P.
AU - Kuivenhoven, Jan Albert
AU - Meulenberg, Janneke M.
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=27744446128&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/16259561
U2 - https://doi.org/10.1089/hum.2005.16.1276
DO - https://doi.org/10.1089/hum.2005.16.1276
M3 - Article
C2 - 16259561
SN - 1043-0342
VL - 16
SP - 1276
EP - 1286
JO - Human gene therapy
JF - Human gene therapy
IS - 11
ER -