ArticleMolecular therapy : the journal of the American Society of Gene Therapy2009
AAV2/8-mediated correction of OTC deficiency is robust in adult but not neonatal Spf(ash) mice.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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72 citing papers in PubMed, 116 citations in OpenAlex.
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- Safe and effective liver-directed AAV-mediated homology-independent targeted integration in mouse models of inherited diseases.Cell reports. Medicine · 2024Article
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- Gene therapy for urea cycle defects: An update from historical perspectives to future prospects.Journal of inherited metabolic disease · 2024Review
- Systemic gene therapy using an AAV44.9 vector rescues a neonatal lethal mouse model of propionic acidemia.Molecular therapy. Methods & clinical development · 2023Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder, is associated with severe hyperammonemia accompanied by a high risk of neurological damage and death in patients presenting with the neonatal-onset form. Contemporary therapies, including liver transplantation, remain inadequate with considerable morbidity, justifying vigorous investigation of alternate therapies. Clinical evidence suggests that as little as 3% normal enzyme activity is sufficient to ameliorate the severe neonatal phenotype, making OTC deficiency an ideal model for the development of liver-targeted gene therapy. In this study, we investigated metabolic correction in neonatal and adult male OTC-deficient Spf(ash) mice following adeno-associated virus (AAV)2/8-mediated delivery of the murine OTC complementary DNA under the transcriptional control of a liver-specific promoter. Substantially supraphysiological levels of OTC enzymatic activity were readily achieved in both adult and neonatal mice following a single intraperitoneal (i.p.) injection, with metabolic correction in adults being robust and life-long. In the neonates, however, full metabolic correction was transient, although modest levels of OTC expression persisted into adulthood. Although not directly testable in Spf(ash) mice, these levels were theoretically sufficient to prevent hyperammonemia in a null phenotype. This loss of expression in the neonatal liver is the consequence of hepatocellular proliferation and presents an added challenge to human therapy.
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