Long-term functional correction of cystathionine β-synthase deficiency in mice by adeno-associated viral gene therapy

Warren D. Kruger, Hyung-Ok Lee, Christiana O. Salami, Stephen M. Kaminsky, Ronald G. Crystal

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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 languageEnglish
Pages (from-to)1382-1392
Number of pages11
JournalJournal of Inherited Metabolic Disease
Volume44
Issue number6
DOIs
StatePublished - 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)

    Equipment/facility: Facility

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