SGSH gene transfer in mucopolysaccharidosis type IIIA mice using canine adenovirus vectors.
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.
Lysosomal Diseases Research Unit, SA Pathology at the WCH, North Adelaide, Australia. adeline.lau@adelaide.edu.au
Adeline A
AA
Lau
John J
JJ
Hopwood
Eric J
EJ
Kremer
Kim M
KM
Hemsley
D006516:Adenoviruses, Canine / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D000914:Antibodies, Viral / Q000032:analysis; D056947:Enzyme Replacement Therapy / Q000379:methods*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006867:Hydrolases / Q000627:therapeutic use*; D051379:Mice; D009084:Mucopolysaccharidosis III / Q000235:genetics / Q000628:therapy*
D000914:Antibodies, Viral; D006867:Hydrolases; C022708:N-sulfoglucosamine sulfohydrolase