Oligonucleotide therapeutic approaches for Huntington disease
Dinah W.Y. Sah, Neil Aronin
Dinah W.Y. Sah, Neil Aronin
Published February 1, 2011
Citation Information: J Clin Invest. 2011;121(2):500-507. https://doi.org/10.1172/JCI45130.
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Oligonucleotide therapeutic approaches for Huntington disease

Abstract

Huntington disease is an autosomal dominant neurodegenerative disorder caused by a toxic expansion in the CAG repeat region of the huntingtin gene. Oligonucleotide approaches based on RNAi and antisense oligonucleotides provide promising new therapeutic strategies for direct intervention through reduced production of the causative mutant protein. Allele-specific and simultaneous mutant and wild-type allele–lowering strategies are being pursued with local delivery to the brain, each with relative merits. Delivery remains a key challenge for translational success, especially with chronic therapy. The potential of disease-modifying oligonucleotide approaches for Huntington disease will be revealed as they progress into clinical trials.

Authors

Dinah W.Y. Sah, Neil Aronin

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Figure 3

Oligonucleotide therapeutic approaches for lowering huntingtin.

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Oligonucleotide therapeutic approaches for lowering huntingtin. Either a...
Either a non–allele-specific or an allele-specific approach can be taken. If a non–allele-specific approach is taken, then the entire huntingtin mRNA transcript can be used to design oligonucleotide sequences with bioinformatics algorithms, generating hundreds of sequences for in vitro potency and selectivity screens. If an allele-specific approach is taken, then either SNP targeting or CAG targeting are possible options. With both of these options, tens of sequences can be designed based on current knowledge of targeting SNPs or the expanded CAG region, for testing in vitro for potency and selectivity.