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Treatment of Cystathionine β-Synthase Deficiency in Mice Using a Minicircle-Based Naked DNA Vector.

Authors
  • Lee, Hyung-Ok1
  • Gallego-Villar, Lorena2
  • Grisch-Chan, Hiu Man3
  • Häberle, Johannes3
  • Thöny, Beat3
  • Kruger, Warren D1
  • 1 Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
  • 2 Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Centre Freiburg, Freiburg, Germany. , (Germany)
  • 3 Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Switzerland. , (Switzerland)
Type
Published Article
Journal
Human Gene Therapy
Publisher
Mary Ann Liebert
Publication Date
Sep 01, 2019
Volume
30
Issue
9
Pages
1093–1100
Identifiers
DOI: 10.1089/hum.2019.014
PMID: 31084364
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Cystathionine β-synthase (CBS) deficiency is a recessive inborn error of metabolism characterized by extremely elevated total homocysteine (tHcy) in the blood. Patients diagnosed with CBS deficiency have a variety of clinical problems, including dislocated lenses, osteoporosis, cognitive and behavioral issues, and a significantly increased risk of thrombosis. Current treatment strategies involve a combination of vitamin supplementation and restriction of foods containing the homocysteine precursor methionine. Here, a mouse model for CBS deficiency (Tg-I278T Cbs-/-) was used to evaluate the potential of minicircle-based naked DNA gene therapy to treat CBS deficiency. A 2.3 kb DNA-minicircle containing the liver-specific P3 promoter driving the human CBS cDNA (MC.P3-hCBS) was delivered into Tg-I278T Cbs-/- mice via a single hydrodynamic tail vein injection. Mean serum tHcy decreased from 351 μM before injection to 176 μM 7 days after injection (p = 0.0005), and remained decreased for at least 42 days. Western blot analysis reveals significant minicircle-directed CBS expression in the liver tissue. Liver CBS activity increased 34-fold (12.8 vs. 432 units; p = 0.0004) in MC.P3-hCBS-injected animals. Injection of MC.P3-hCBS in young mice, subsequently followed for 202 days, showed that the vector can ameliorate the mouse homocystinuria alopecia phenotype. The present findings show that minicircle-based gene therapy can lower tHcy in a mouse model of CBS deficiency.

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