AAV gene therapy as a means to increase apolipoprotein (Apo) A-I and high-density lipoprotein-cholesterol levels: correction of murine ApoA-I deficiency

Autor: Elisabeth M Comijn, Karin van den Oever, Stefan F C Vaessen, Jeroen A. Sierts, Robert Jan Veldman, Jolanda Snapper, Stuart G. Beattie, Jaap Twisk, Jan Albert Kuivenhoven
Přispěvatelé: Experimental Vascular Medicine, Other departments, ACS - Amsterdam Cardiovascular Sciences, Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM)
Jazyk: angličtina
Rok vydání: 2009
Předmět:
Apolipoprotein B
Genetic enhancement
Cytomegalovirus
medicine.disease_cause
Weight Gain
chemistry.chemical_compound
Mice
High-density lipoprotein
Drug Discovery
Promoter Regions
Genetic
Hypoalphalipoproteinemia
Adeno-associated virus
Genetics (clinical)
biology
Dependovirus
Cholesterol
Enhancer Elements
Genetic
Phenotype
Liver
Organ Specificity
Injections
Intravenous
Molecular Medicine
lipids (amino acids
peptides
and proteins)
Intravenous
Plasmids
medicine.medical_specialty
HDL
Enhancer Elements
Genetic Vectors
Gene delivery
Injections
Promoter Regions
Genetic
Internal medicine
Insertional
Genetics
medicine
Animals
Humans
Serotyping
Molecular Biology
Apolipoprotein A-I
Body Weight
Cholesterol
HDL
Genetic Therapy
medicine.disease
Molecular biology
Mutagenesis
Insertional
Endocrinology
chemistry
Mutagenesis
biology.protein
Lipoprotein
Zdroj: journal of gene medicine, 11(8), 697-707. John Wiley and Sons Ltd
Journal of gene medicine, 11(8), 697-707. Wiley
ISSN: 1099-498X
Popis: BACKGROUND: Inherited apolipoprotein (Apo) A-I deficiency is an orphan disorder characterized by high-density lipoprotein (HDL)-cholesterol deficiency and premature atherosclerosis. Constitutive over-expression of ApoA-I might provide a means to treat this disease. The present study provides a comprehensive evaluation of adeno-associated virus (AAV)-mediated ApoA-I gene delivery to express human (h)ApoA-I and correct the low HDL-cholesterol phenotype associated with ApoA-I deficiency.METHODS: In an effort to maximize AAV-mediated gene expression, we performed head-to-head comparisons of recombinant AAVs with pseudotype capsids 1, 2, 6 and 8 administered by different routes with the use of five different liver-specific promoters in addition to cytomegalovirus as single-stranded or as self-complementary (sc) AAV vectors.RESULTS: Intravenous administration of 1 x 10(13) gc/kg scAAV8, in combination with the liver-specific promoter LP1, in female ApoA-I(-/-) mice resulted in hApoA-I expression levels of 634 +/- 69 mg/l, which persisted for the duration of the study (15 weeks). This treatment resulted in full recovery of HDL-cholesterol levels with correction of HDL particle size and apolipoprotein composition. In addition, we observed increased adrenal cholesterol content and a significant increase in bodyweight in treated mice.CONCLUSIONS: The present study demonstrates that systemic delivery of a scAAV8 vector provides a means for efficient liver expression of hApoA-I, thereby correcting the lipid abnormalities associated with murine ApoA-I deficiency. Importantly, the study demonstrates that AAV-based gene therapy can be used to express therapeutic proteins at a high level for a prolonged period of time and, as such, provides a basis for further development of this strategy to treat hApoA-I deficiency.
Databáze: OpenAIRE
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