Open AccessTreatment of Cystathionine β-Synthase Deficiency in Mice Using a Minicircle-Based Naked DNA Vector
Author(s) -
HyungOk Lee,
Lorena Gallego,
Hiu Man GrischChan,
Johannes Häberle,
Beat Thöny,
Warren D. Kruger
Publication year - 2019
Publication title -
human gene therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.633
H-Index - 149
eISSN - 1557-7422
pISSN - 1043-0342
DOI - 10.1089/hum.2019.014
Subject(s) - cystathionine beta synthase , minicircle , homocystinuria , homocysteine , endocrinology , medicine , biology , genetic enhancement , microbiology and biotechnology , methionine , gene , biochemistry , amino acid
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.