Antisense gene therapy for neurodegenerative disease?

Diseases resulting from defects in a single gene may be more amenable to treatment by conventional gene therapy strategies than idiopathic or polygenic disorders. We have attempted to reduce the expression in vivo of the Huntington's disease gene protein, Huntingtin, using an 18-mer fluoroscein-labeled phosphorothioroated antisense oligodeoxynucleotide (ODN) targeted against the start site of the first exon of the IT15 gene. Animals were given repeated intrastriatal infusions (5 mu l of a 100 nmol/mu l solution daily over 4 days) of the antisense ODN. The treatments ended on Day 5 and the tissue was processed for immunohistochemical and Western blot analysis. The fluorescein-labeled ODN appeared to penetrate several cells and did not cause any obvious toxicity to the neurons. The average reduction in levels of Huntingtin (16.9 +/- 7.2%) did not differ significantly between striatal tissue of antisense ODN-treated animals compared to those treated with a sense ODN or vehicle. Improved methods for molecular modifications of the IT15 gene may be needed for therapeutic initiatives. (C) 1997 Academic Press.