FCCC LOGO Faculty Publications
Lee HO , Gallego-Villar L , Grisch-Chan HM , Haeberle J , Thony B , Kruger WD
Treatment of CBS deficiency in mice using a minicircle-based naked DNA vector
Hum Gene Ther. 2019 Sep;30(9) :1093-1100
PMID: 31084364    PMCID: PMC6761586    URL: https://www.ncbi.nlm.nih.gov/pubmed/31084364
Back to previous list
Cystathionine beta-synthase (<i>CBS</i>) deficiency is a recessive inborn error of metabolism characterized by extremely elevated total homocysteine (tHcy) in blood. Patients diagnosed with CBS deficiency have a variety of clinical problems in 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 we use a mouse model for CBS deficiency (<i>Tg-I278T Cbs<sup>-/-</sup></i>) 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 <i>CBS</i> cDNA (MC.P3-hCBS) was delivered into <i>Tg-I278T Cbs<sup>-/-</sup> </i>mice via a single hydrodynamic tail vein (HTV) injection. Mean serum tHcy decreased from 351 muM before injection to 176 muM (p=0.0005) seven days after injection, 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, shows that the vector can ameliorate the mouse homocystinuria alopecia phenotype. Our findings show that minicircle-based gene therapy can lower tHcy in a mouse model of CBS deficiency..
1557-7422 Lee, Hyung-Ok Gallego-Villar, Lorena Grisch-Chan, Hiu Man Haeberle, Johannes Thony, Beat Kruger, Warren P30 CA006927/CA/NCI NIH HHS/ Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Hum Gene Ther. 2019 Sep;30(9):1093-1100. doi: 10.1089/hum.2019.014. Epub 2019 Jun 13.