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Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin gene (HTT), which codes for the pathologic mutant HTT (mHTT) protein. Since normal HTT is thought to be important for brain function, we engineered zinc finger protein transcription factors (ZFP-TFs) to target the pathogenic CAG repeat and selectively lower mHTT as a therapeutic strategy. Using patient-derived fibroblasts and neurons, we demonstrate that ZFP-TFs selectively repress >99% of HD-causing alleles over a wide dose range while preserving expression of >86% of normal alleles. Other CAG-containing genes are minimally affected, and virally delivered ZFP-TFs are active and well tolerated in HD neurons beyond 100 days in culture and for at least nine months in the mouse brain. Using three HD mouse models, we demonstrate improvements in a range of molecular, histopathological, electrophysiological and functional endpoints. Our findings support the continued development of an allele-selective ZFP-TF for the treatment of HD.

There are approximately 7000 known rare and orphan diseases, over a third of which affect the central nervous system, virtually all do not have adequate treatment options. Shire is committed to developing innovative medicines to treat the fundamental biochemical abnormalities that result in pathologies caused by lysosomal storage disorders and other rare neurological diseases by selecting the right biological target based on extensive knowledge of disease pathophysiology and the right therapeutic modality from our array of technology platforms that includes antibodies, modified RNA, small molecules, gene therapy and protein therapeutics. This approach is particularly relevant for Huntington’s disease (HD), a rare and fatal neurodegenerative disease caused by a CAG trinucleotide repeat expansion in exon 1 of one copy of the Huntingtin (Htt) gene, resulting in expression of an aggregation-prone mutant protein. As this mutant protein is believed to be a primary cause of the pathophysiology in HD, Htt-lowering approaches are being explored using various technologies. Here, we will describe the use of an engineered zinc-finger protein transcription factor (ZFP TF) that preferentially down-regulates expression from the disease-causing copy of the Htt gene relative to the normal, unexpanded copy of the gene in both in vitro and in vivo HD models. Results presented here support the further development of allele-specific ZFP TFs as a potential therapy for HD.

Abstracts from the 3rd Conference on Aneuploidy and Cancer: Clinical and Experimental Aspects