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Hum Mol Genet. 2016 Apr 15;25(R1):R53-64. doi: 10.1093/hmg/ddv442. Epub 2015 Oct 26.

Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington's disease and spinocerebellar ataxia.

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Raymond G. Perlman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Isis Pharmaceuticals, Carlsbad, CA, USA.
Department of Neurology, Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA and Deparment of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, USA


RNA-targeting approaches are emerging as viable therapeutics that offer an alternative method to modulate traditionally 'undrugable' targets. In the case of dominantly inherited neurodegenerative diseases, gene suppression strategies can target the underlying cause of these intractable disorders. Polyglutamine diseases are caused by CAG expansions in discrete genes, making them ideal candidates for gene suppression therapies. Here, we discuss the current state of gene suppression approaches for Huntington's disease and the spinocerebellar ataxias, including the use of antisense oligonucleotides, short-interfering RNAs, as well as viral vector-mediated delivery of short hairpin RNAs and artificial microRNAs. We focus on lessons learned from preclinical studies investigating gene suppression therapies for these disorders, particularly in rodent models of disease and in non-human primates. In animal models, recent advances in gene suppression technologies have not only prevented disease progression in a number of cases, but have also reversed existing disease, providing evidence that reducing the expression of disease-causing genes may be of benefit in symptomatic patients. Both allele- and non-allele-specific approaches to gene suppression have made great strides over the past decade, showing efficacy and safety in both small and large animal models. Advances in delivery techniques allow for broad and durable suppression of target genes, have been validated in non-human primates and in some cases, are currently being evaluated in human patients. Finally, we discuss the challenges of developing and delivering gene suppression constructs into the CNS and recent advances of potential therapeutics into the clinic.

[Indexed for MEDLINE]
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