| First Author | Ross CJ | Year | 2004 |
| Journal | Hum Gene Ther | Volume | 15 |
| Issue | 9 | Pages | 906-19 |
| PubMed ID | 15353045 | Mgi Jnum | J:107622 |
| Mgi Id | MGI:3621571 | Doi | 10.1089/hum.2004.15.906 |
| Citation | Ross CJ, et al. (2004) Long-term correction of murine lipoprotein lipase deficiency with AAV1-mediated gene transfer of the naturally occurring LPL(S447X) beneficial mutation. Hum Gene Ther 15(9):906-19 |
| abstractText | Human lipoprotein lipase (LPL) deficiency causes profound hypertriglyceridemia and life-threatening pancreatitis. We recently developed an adult murine model for LPL deficiency: LPL -/- mice display grossly elevated plasma triglyceride (TG) levels (>200-fold) and very low high-density lipoprotein cholesterol (HDL-C < 10% of normal). We used this animal model to test the efficacy of adeno-associated virus-mediated expression of hLPL(S447X) (AAV1-LPL(S447X)) in muscle for the treatment of LPL deficiency. Intramuscular administration of AAV1-LPL(S447X) resulted in dose-dependent expression of hLPL protein and LPL activity (up to 33% of normal murine levels) in postheparin plasma. Remarkably, visible hyperlipidemia was resolved within 1 week; plasma TG was reduced to near-normal levels (from 99.0 to 1.8 mmol/L), and plasma HDL-C was increased 6-fold (from 0.2 to 1.1 mmol/L). At 8 months after administration of AAV1-LPL(S447X), an intravenous lipid challenge showed efficient, near-normal clearance of plasma TG. Histologic analyses of injected muscle further indicated that abnormal muscle morphology observed in LPL -/- mice was reversed after treatment. Expression of therapeutic levels of LPL(S447X), and the subsequent beneficial effect on plasma lipid levels, has lasted for more than 1 year. We therefore conclude that AAV1-mediated transfer of LPL(S447X) into murine skeletal muscle results in long-term near-correction of dyslipidemia associated with LPL deficiency. |
