Gene Therapy for Ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by neurodegeneration, immunodeficiency, cancer predisposition, genome instability, and radiation sensitivity. Previous research has shown that it is possible to correct the hereditary deficiency A-T by DNA transfection of the ATM cDNA in cell culture, but the large size of this cDNA (9 kb) limits the use of many vector types for gene replacement. HSV-1 amplicon vectors provide a means to deliver large genes (up to 150 kb) to cells efficiently and without toxicity. We have constructed the first viral vector, an HSV-1 amplicon, carrying the full-length ATM cDNA, and have shown correction of the cellular phenotype in human A-T cells. Our current work focuses on gene delivery in A-T mouse models to correct deficiencies in different tissues and to develop new vectors to achieve targeted stable gene integration of the ATM cDNA for gene replacement.

The development of a vector system for delivery of the ATM cDNA to cells, in culture and in vivo, will help elucidate the functions of the normal protein in different cell types, and enhance the potential for correction of neurological and immunological, as well as other abnormalities in A-T by gene therapy

 

Related papers

Cortes, M.L., Bakkenist, C., Di Maria, M.V., Kastan, M.B., Breakefield, X.O. HSV-1 amplicon vector-mediated expression of ATM cDNA and correction of the ataxia telangiectasia cellular phenotype. Gene Therapy, 10, 1321-1327, 2003.

Panta, G.R., Kaur, S., Cavin, L.G., Cortes, M.L, Mercurio, F., Lothstein, L., Sweatman, T.W., Israel, M., Arsura, M. ATM and the catalytic subunit of DNA-dependent protein kinase activate NF-kappaB through a common MEK/extracellular signal-regulated kinase/p90(rsk) signaling pathway in response to distinct forms of DNA damage. Moll Cell Biol 24 (5), 1823-1835, 2004.

Bagley, J., Cortes, M.L.,, Breakefield, X.O., Iacomini, J. Bone marrow transplantation restores immune system function and prevents lymphoma in Atm-deficient mice. Blood 104 (2), 572-578, 2004.