Correction of Feline Lipoprotein Lipase Deficiency with Adeno-Associated Virus Serotype 1-Mediated Gene Transfer of the Lipoprotein Lipase S447X Beneficial Mutation

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Abstract
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 LPLS447X 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-LPLS447X 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-LPLS447X (1 × 1011–1.7 × 1012 genome copies [GC]/kg), combined with oral doses of cyclophosphamide (0–200 mg/m2 per week) to inhibit an immune response against hLPL. Within 3–7 days after administration of ≥5 × 1011 GC of AAV1-LPLS447X 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 × 1011 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 × 1010–1 × 1012 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 LPLS447X in muscle is an effective means to correct the hypertriglyceridemia associated with feline LPL deficiency.