title: Correction of feline lipoprotein lipase deficiency with adeno-associated virus serotype 1-mediated gene transfer of the lipoprotein lipase S447X beneficial mutation.
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 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.
authors.affiliation: Department of Medical Genetics, University of British Columbia, and Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada V5Z 4H4.
authors.forename: Colin J D
authors.initials: CJ
authors.lastname: Ross
authors.forename: Jaap
authors.initials: J
authors.lastname: Twisk
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Bakker
authors.forename: Fudan
authors.initials: F
authors.lastname: Miao
authors.forename: Dennis
authors.initials: D
authors.lastname: Verbart
authors.forename: Jaap
authors.initials: J
authors.lastname: Rip
authors.forename: Tamara
authors.initials: T
authors.lastname: Godbey
authors.forename: Paul
authors.initials: P
authors.lastname: Dijkhuizen
authors.forename: Wim T J M C
authors.initials: WT
authors.lastname: Hermens
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: Janneke M
authors.initials: JM
authors.lastname: Meulenberg
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000818:Animals; D000917:Antibody Formation; D002415:Cats; D003520:Cyclophosphamide / Q000627:therapeutic use; D000229:Dependovirus / Q000235:genetics*; D005240:Feasibility Studies; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D015228:Hypertriglyceridemia / Q000235:genetics / Q000628:therapy*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D017354:Point Mutation; D019076:Transgenes / Q000276:immunology; D014280:Triglycerides / Q000097:blood
chemical_list: D007166:Immunosuppressive Agents; D008055:Lipids; D014280:Triglycerides; D003520:Cyclophosphamide; D008071:Lipoprotein Lipase