Phenotypic correction of feline lipoprotein lipase deficiency by adenoviral gene transfer

Guoqing Liu, Katherine J.D. Ashbourne Excoffon, Janet E. Wilson, Bruce M. McManus, Quinton Rogers, Li Miao, John J.P. Kastelein, M. E.Suzanne Lewis, Michael R. Hayden

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Previous studies have revealed that adenovirus-mediated ectopic liver expression of human LPL (huLPL) can efficiently mediate plasma triacylglycerol (TG) catabolism in mice despite its native expression in adipose and muscle tissue. We aimed to explore the feasibility of liver- directed gene transfer and enzyme replacement for human LPL deficiency in a larger, naturally occurring feline animal model of complete LPL deficiency that is remarkably similar in phenotype to the human disorder. A cohort of LPL-deficient (LPL -/-) cats was given an intravenous injection of 8 X 109 PFU/kg of a CMV promoter/enhancer-driven, E1/E3-deleted adenoviral (Ad) vector containing a 1.36-kb huLPL cDNA (Ad-LPL) or reporter alkaline phosphatase gene (Ad-AP). After Ad-LPL administration, active, heparin- releasable huLPL was readily detected along with a 10-fold reduction in plasma TGs, disappearance of plasma TG-rich lipoproteins up to day 14, and enhanced clearance of an excess intravenous fat load on day 9. However, antibody against the huLPL protein was detected on day 14 in cats receiving Ad-LPL and adenovirus-specific neutralizing antibody was present 7 days after gene transfer in both cat cohorts. Tissue-specific expression of the huLPL transgene relative to controls was confirmed by RT-PCR. While huLPL expression was evident in the liver, other tissues including spleen and lung expressed huLPL message, in direct correlation with histological evidence of increased Oil red O (ORO)-positive neutral lipid influx. In contrast, intravenous LPL enzyme replacement therapy (ERT) led to rapid disappearance of 9000 mU/kg of active bovine LPL enzyme from the circulation, with t 1/2 occurring at <10 min in two LPL-/- cats. Heparin injection 1 hr later released <10% of the original bovine LPL, further indicating its rapid systemic clearance, inactivation, or degradation as well as its ineffectiveness as a viable therapeutic alternative for complete LPL deficiency. Although LPL gene transfer and expression via this first- generation Ad vector was limited by the immune response against both the human LPL protein and adenovirus our results clearly provide a key advance supporting further development of LPL gene therapy as a viable therapeutic option for clinical LPL deficiency.

Original languageEnglish (US)
Pages (from-to)21-32
Number of pages12
JournalHuman Gene Therapy
Volume11
Issue number1
DOIs
StatePublished - Jan 24 2000

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Hyperlipoproteinemia Type I
Felidae
Genes
Cats
Adenoviridae
Heparin
Liver
Triglycerides
Enzyme Replacement Therapy
Human Adenoviruses
Enzymes
Neutralizing Antibodies
Transgenes
Intravenous Injections
Genetic Therapy
Lipoproteins
Alkaline Phosphatase
Adipose Tissue
Spleen
Animal Models

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Liu, G., Ashbourne Excoffon, K. J. D., Wilson, J. E., McManus, B. M., Rogers, Q., Miao, L., ... Hayden, M. R. (2000). Phenotypic correction of feline lipoprotein lipase deficiency by adenoviral gene transfer. Human Gene Therapy, 11(1), 21-32. https://doi.org/10.1089/10430340050016120

Phenotypic correction of feline lipoprotein lipase deficiency by adenoviral gene transfer. / Liu, Guoqing; Ashbourne Excoffon, Katherine J.D.; Wilson, Janet E.; McManus, Bruce M.; Rogers, Quinton; Miao, Li; Kastelein, John J.P.; Lewis, M. E.Suzanne; Hayden, Michael R.

In: Human Gene Therapy, Vol. 11, No. 1, 24.01.2000, p. 21-32.

Research output: Contribution to journalArticle

Liu, G, Ashbourne Excoffon, KJD, Wilson, JE, McManus, BM, Rogers, Q, Miao, L, Kastelein, JJP, Lewis, MES & Hayden, MR 2000, 'Phenotypic correction of feline lipoprotein lipase deficiency by adenoviral gene transfer', Human Gene Therapy, vol. 11, no. 1, pp. 21-32. https://doi.org/10.1089/10430340050016120
Liu, Guoqing ; Ashbourne Excoffon, Katherine J.D. ; Wilson, Janet E. ; McManus, Bruce M. ; Rogers, Quinton ; Miao, Li ; Kastelein, John J.P. ; Lewis, M. E.Suzanne ; Hayden, Michael R. / Phenotypic correction of feline lipoprotein lipase deficiency by adenoviral gene transfer. In: Human Gene Therapy. 2000 ; Vol. 11, No. 1. pp. 21-32.
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