SGSH gene transfer in mucopolysaccharidosis type IIIA mice using canine adenovirus vectors

A. A. Lau , J. J. Hopwood , E. J. Kremer (1) , K. M. Hemsley

1 IGMM - Institut de Génétique Moléculaire de Montpellier

Many viral backbones have been used as gene transfer vectors. However, the efficacy of therapy based on human-derived vectors may be limited by the high incidence of pre-existing humoral and cellular memory immunity. To circumvent some of the clinical disadvantages of vectors derived from common human pathogens, we have used an E1-deleted vector derived from a xenogenic adenovirus, canine adenovirus serotype 2 (CAV-2) to ameliorate neuropathological changes associated with the lysosomal storage disorder, mucopolysaccharidosis type IIIA (MPS IIIA). This presently untreatable condition is caused by N-sulfoglucosamine sulfohydrolase (SGSH) deficiency and is characterized by heparan sulfate accumulation and progressive neurodegeneration. Injection of CAV-SGSH-GFP into the thalamus of adult MPS IIIA mouse brain resulted in short-term gene expression. In contrast, intra-ventricular injection of newborn mice yielded dose-dependent transgene expression which persisted for at least 20-weeks and improved neuropathology. Together, these studies suggest that this E1-deleted CAV-2 vector is capable of mediating regional medium-term gene expression and facilitating improvements in neuropathology in MPS IIIA mice.

Mots clés: Adenoviruses; Canine/*genetics/immunology Animals Animals; Newborn Antibodies; Viral/analysis Enzyme Replacement Therapy/*methods Gene Transfer Techniques Genetic Vectors Hydrolases/*therapeutic use Mice Mucopolysaccharidosis III/genetics/*therapy

Domaines: Biochimie, Biologie Moléculaire

A. A. Lau, J. J. Hopwood, E. J. Kremer, K. M. Hemsley. SGSH gene transfer in mucopolysaccharidosis type IIIA mice using canine adenovirus vectors. Molecular Genetics and Metabolism, 2010, 100 (2), pp.168--75. ⟨10.1016/j.ymgme.2010.02.006⟩. ⟨hal-02193616⟩