Huntington disease (HD) is caused by a CAG trinucleotide expansion in the huntingtin gene (HTT), which codes for the pathologic mutant HTT (mHTT) protein. Here, the authors engineered zinc finger protein transcription factors (ZFP-TFs) to target the CAG repeat and selectively repress levels of mHTT. In patient-derived fibroblasts and neurons, ZFP-TFs selectively repressed >99% of HD-causing alleles while preserving expression of >86% of normal alleles. This allele selective approach is essential as normal HTT is thought to have an important role in brain function.
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Zeitler, B. et al. Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. Nat. Med. 25, 1131–1142 (2019)
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Leake, I. Repressing mutant proteins. Nat Rev Neurosci 20, 513 (2019). https://doi.org/10.1038/s41583-019-0211-8
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DOI: https://doi.org/10.1038/s41583-019-0211-8
