AAV gene therapy corrects OTC deficiency and prevents liver fibrosis in aged
OTC-knock out heterozygous mice
#MMPMID28283349
Wang L
; Bell P
; Morizono H
; He Z
; Pumbo E
; Yu H
; White J
; Batshaw ML
; Wilson JM
Mol Genet Metab
2017[Apr]; 120
(4
): 299-305
PMID28283349
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Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder of the urea
cycle. Hemizygous males and heterozygous females may experience life-threatening
elevations of ammonia in blood and brain, leading to irreversible cognitive
impairment, coma, and death. Recent evidence of acute liver failure and
fibrosis/cirrhosis is also emerging in OTC-deficient patients. Here, we
investigated the long-term consequences of abnormal ureagenesis in female mice
heterozygous (Het) for a null mutation in the OTC gene. Two-month-old Het OTC
knockout (KO) mice received a single dose of self-complementary adeno-associated
virus (AAV) encoding a codon-optimized human OTC gene at 1×10(10), 3×10(10), or
1×10(11) vector genome copies per mouse. We compared liver pathology from
18-month-old treated Het OTC-KO mice, age-matched untreated Het OTC-KO mice, and
WT littermates, and assessed urinary orotic acid levels and vector genome copies
in liver at 4, 10, and 16months following vector administration. Het OTC-KO
female mice showed evidence of liver inflammation and the eventual development of
significant fibrosis. Treatment with AAV gene therapy not only corrected the
underlying metabolic abnormalities, but also prevented the development of liver
fibrosis. Our study demonstrates that early treatment of OTC deficiency with gene
therapy may prevent clinically relevant consequences of chronic liver damage from
developing.
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