Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease.

Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease.

Publication date: Jul 01, 2019

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.

Zeitler, B., Froelich, S., Marlen, K., Shivak, D.A., Yu, Q., Li, D., , Pearl, Miller, J.C., Zhang, L., Paschon, D.E., Hinkley, S.J., , Ankoudinova, Lam, S., Guschin, D., Kopan, L., Cherone, J.M., Nguyen, H.B., Qiao, G., Ataei, Y., Mendel, M.C., Amora, R., Surosky, R., Laganiere, J., Vu, B.J., Narayanan, A., Sedaghat, Y., Tillack, K., Thiede, C., G”artner, A., Kwak, S., Bard, J., Mrzljak, L., Park, L., Heikkinen, T., Lehtim”aki, K.K., Svedberg, M.M., H”aggkvist, J., Tari, L., T’oth, M., Varrone, A., Halldin, C., Kudwa, A.E., Ramboz, S., Day, M., Kondapalli, J., Surmeier, D.J., Urnov, F.D., Gregory, P.D., Rebar, E.J., , Mu~noz-Sanju’an, and Zhang, H.S. Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. 06557. 2019 Nat Med.

Concepts Keywords
Allele Huntington’s disease
Alleles Human genetics
Brain Human biology
Electrophysiological HD
Fibroblasts HTT
Histopathological Trinucleotide repeat disorder
Huntingtin Branches of biology
Huntington Huntingtin
Mutant Neurodegenerative disorder
Neurodegenerative Disorder
Neurons
Pathogenic
Protein
Virally

Semantics

Type Source Name
disease MESH development
gene UNIPROT ZKSCAN7
gene UNIPROT ZHX1-C8orf76
drug DRUGBANK Zinc
gene UNIPROT SLC6A4
disease MESH neurodegenerative disorder
gene UNIPROT HTT
disease MESH repression

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