AAV gene therapy as a means to increase apolipoprotein (Apo) A-I and high-density lipoprotein-cholesterol levels: correction of murine ApoA-I deficiency.
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.
Department of Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
Stefan F C
SF
Vaessen
Robert Jan
RJ
Veldman
Elisabeth M
EM
Comijn
Jolanda
J
Snapper
Jeroen A
JA
Sierts
Karin
K
van den Oever
Stuart G
SG
Beattie
Jaap
J
Twisk
Jan Albert
JA
Kuivenhoven
D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood* / Q000172:deficiency* / Q000235:genetics; D001835:Body Weight; D008076:Cholesterol, HDL / Q000097:blood*; D003587:Cytomegalovirus / Q000235:genetics; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D051379:Mice; D016254:Mutagenesis, Insertional; D009928:Organ Specificity; D010641:Phenotype; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012703:Serotyping; D015430:Weight Gain
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL