Correction of Feline Lipoprotein Lipase Deficiency with Adeno-Associated Virus Serotype 1-Mediated Gene Transfer of the Lipoprotein Lipase S447X Beneficial Mutation
| Autor: | Colin J. D. Ross, Michael R. Hayden, Paul A. Dijkhuizen, Janneke M. Meulenberg, John J.P. Kastelein, Jaap Rip, Wim T. J. M. C. Hermens, Andrew C. Bakker, Fudan Miao, Dennis Verbart, Jaap Twisk, Jan Albert Kuivenhoven, Tamara Godbey |
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| Přispěvatelé: | Amsterdam Cardiovascular Sciences, Vascular Medicine, Experimental Vascular Medicine |
| Rok vydání: | 2006 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Genetic enhancement Biology medicine.disease_cause Lipoprotein lipase deficiency Internal medicine medicine Genetics Animals Point Mutation Transgenes Muscle Skeletal Cyclophosphamide Adeno-associated virus Molecular Biology Triglycerides Hypertriglyceridemia Lipoprotein lipase Genetic transfer digestive oral and skin physiology Gene Transfer Techniques nutritional and metabolic diseases Immunosuppression Genetic Therapy Dependovirus medicine.disease Lipids Lipoprotein Lipase Endocrinology Biochemistry Antibody Formation Cats Feasibility Studies Molecular Medicine lipids (amino acids peptides and proteins) Immunosuppressive Agents Dyslipidemia |
| Zdroj: | Human gene therapy, 17(5), 487-499. Mary Ann Liebert Inc. |
| ISSN: | 1043-0342 |
| DOI: | 10.1089/hum.2006.17.ft-198 |
| Popis: | Human lipoprotein lipase (hLPL) deficiency, for which there currently exists no adequate treatment, leads to excessive plasma triglycerides (TGs), recurrent abdominal pain, and life-threatening pancreatitis. We have shown that a single intramuscular administration of adeno-associated virus (AAV) serotype 1 vector, encoding the human LPL(S447X) variant, results in complete, long-term normalization of dyslipidemia in LPL(/) mice. As a prelude to gene therapy for human LPL deficiency, we tested the efficacy of AAV1-LPL(S447X) in LPL(/) cats, which demonstrate hypertriglyceridemia (plasma TGs, >10,000 mg/dl) and clinical symptoms similar to LPL deficiency in humans, including pancreatitis. Male LPL(/) cats were injected intramuscularly with saline or AAV1-LPL(S447X) (1 x 10(11)-1.7 x 10(12) genome copies [GC]/kg), combined with oral doses of cyclophosphamide (0-200 mg/m(2) per week) to inhibit an immune response against hLPL. Within 3-7 days after administration of >or=5 x 10(11) GC of AAV1-LPL(S447X) per kilogram, the visible plasma lipemia was completely resolved and plasma TG levels were reduced by >99% to normal levels (10-20 mg/dl); intermediate efficacy (95% reduction) was achieved with 1 x 10(11) GC/kg. Injection in two sites, greatly limiting the amount of transduced muscle, was sufficient to completely correct the dyslipidemia. By varying the dose per site, linear LPL expression was demonstrated over a wide range of local doses (4 x 10(10)-1 x 10(12) GC/site). However, efficacy was transient, because of an anti-hLPL immune response blunting LPL expression. The level and duration of efficacy were significantly improved with cyclophosphamide immunosuppression. We conclude that AAV1-mediated delivery of LPL(S447X) in muscle is an effective means to correct the hypertriglyceridemia associated with feline LPL deficiency. |
| Databáze: | OpenAIRE |
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