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Long-term functional correction of cystathionine ß-synthase deficiency in mice by adeno-associated viral gene therapy.
Lee, Hyung-Ok; Salami, Christiana O; Sondhi, Dolan; Kaminsky, Stephen M; Crystal, Ronald G; Kruger, Warren D.
Affiliation
  • Lee HO; Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
  • Salami CO; Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA.
  • Sondhi D; Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA.
  • Kaminsky SM; Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA.
  • Crystal RG; Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA.
  • Kruger WD; Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
J Inherit Metab Dis ; 44(6): 1382-1392, 2021 11.
Article in En | MEDLINE | ID: mdl-34528713
Cystathionine ß-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.
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Full text: 1 Database: MEDLINE Main subject: Genetic Therapy / Dependovirus / Cystathionine beta-Synthase / Genetic Vectors / Homocystinuria Type of study: Prognostic_studies / Risk_factors_studies Language: En Journal: J Inherit Metab Dis Year: 2021 Type: Article Affiliation country: United States

Full text: 1 Database: MEDLINE Main subject: Genetic Therapy / Dependovirus / Cystathionine beta-Synthase / Genetic Vectors / Homocystinuria Type of study: Prognostic_studies / Risk_factors_studies Language: En Journal: J Inherit Metab Dis Year: 2021 Type: Article Affiliation country: United States