Abstract
Cystathionine β-synthase (CBS) deficiency is a recessive inborn error of sulfur metabolism characterized by elevated blood levels of total homocysteine (tHcy). Patients diagnosed with CBS deficiency are currently treated by a combination of vitamin supplementation and restriction of foods containing the homocysteine precursor methionine, but the effectiveness of this therapy is limited due to poor compliance. A mouse model for CBS deficiency (Tg-I278T Cbs−/−) was used to evaluate a potential gene therapy approach to treat CBS deficiency utilizing an AAVrh.10-based vector containing the human CBS cDNA downstream of the constitutive, strong CAG promoter (AAVrh.10hCBS). Mice were administered a single dose of virus and followed for up to 1 year. The data demonstrated a dose-dependent increase in liver CBS activity and a dose-dependent decrease in serum tHcy. Liver CBS enzyme activity at 1 year was similar to Cbs+/− control mice. Mice given the highest dose (5.6 × 1011 genomes/mouse) had mean serum tHcy decrease of 97% 1 week after injection and an 81% reduction 1 year after injection. Treated mice had either full- or substantial correction of alopecia, bone loss, and fat mass phenotypes associated with Cbs deficiency in mice. Our findings show that AAVrh.10-based gene therapy is highly effective in treating CBS deficiency in mice and supports additional pre-clinical testing for eventual use human trials.
Original language | English |
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Pages (from-to) | 1382-1392 |
Number of pages | 11 |
Journal | Journal of Inherited Metabolic Disease |
Volume | 44 |
Issue number | 6 |
DOIs | |
State | Published - Nov 2021 |
Keywords
- Animals
- Cystathionine beta-Synthase/blood
- Dependovirus/genetics
- Disease Models, Animal
- Female
- Gene Expression
- Gene Transfer Techniques
- Genetic Therapy
- Genetic Vectors/administration & dosage
- Homocystinuria/genetics
- Liver/metabolism
- Male
- Mice
- Mice, Knockout
- Phenotype
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Laboratory Animal Facility
Patterson, MLAS, CMAR, RLATg, ILAM, K. S. (Director), Pimble, AS, A. T. (Manager) & Tuohy VMD, K. (Staff)
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