Recombinant adeno-associated virus mediated gene transfer in a mouse model for homocystinuria.
- Author:
Eun Sook PARK
1
;
Hyun Jeong OH
;
Warren D KRUGER
;
Sung Chul JUNG
;
Jin Sung LEE
Author Information
1. Brain Korea 21 Project for Medical Science, Yonsei University, Seoul 120-752, Korea. nsunglee@yumc.yonsei.ac.kr
- Publication Type:Original Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
- Keywords:
cystathionine beta-synthase;
dependovirus;
gene therapy;
homocysteine;
homocystinuria;
mouse
- MeSH:
Survival Rate;
Mice;
Immunohistochemistry;
Humans;
Homocystinuria/enzymology/*genetics/pathology/therapy;
Homocysteine/blood;
Gene Transfer Techniques;
Gene Therapy;
Disease Models, Animal;
Dependovirus/*genetics;
DNA, Recombinant/genetics;
Cystathionine beta-Synthase/genetics/metabolism;
Cell Line;
Animals
- From:Experimental & Molecular Medicine
2006;38(6):652-661
- CountryRepublic of Korea
- Language:English
-
Abstract:
Homocystinuria is a metabolic disorder caused by a deficiency of cystathionine b-synthase (CBS). The major clinical symptoms of this disease are mental retardation, lens dislocation, vascular disease with life-threatening thromboembolisms, and skeletal deformities. The major treatments for CBS deficiency include pharmacologic doses of pyridoxine or dietary restriction of methionine. There is currently no effective long-term treatment to lower the elevated plasma levels of homocysteine. However, gene therapy could be an effective novel approach for the treatment of homocystinuria. A recombinant adeno- associated virus vector carrying human CBS cDNA (rAAV-hCBS) was constructed and administered to CBS-/- mice by intramuscular (IM) and intraperitoneal (IP) injections. Serum homocysteine concentrations significantly decreased in treated mice compared with age-matched controls two weeks after treatment. The treated CBS-/- mice had life spans 3-7 days longer compared with untreated CBS-/- mice. In CBS-/- mice treated with rAAV-hCBS via IP injection, the vector was detected in all organs examined including liver, spleen, and kidney, and CBS gene expression was observed by immunohistochemical staining in the liver. These results indicate the efficacy of gene delivery and demonstrate the possibility of gene therapy mediated by AAV gene transfer in this mouse model of homocystinuria.
