ZFP-TFs gene regulation technology designed by Sangamo therapeutics could repressed allele specific gene without affecting the normal allele.

Sangamo therapeutics on July 1 announced publication of a manuscript in Nature Medicine on the activity of allele-specific Zinc Finger Proteins (ZFP-TFs) in models of Huntington’s Disease. The data which was published online on July 1 will appear in the July 2019 issue of Nature Medicine.

Scientists from Sangamo and its collaborators from CHDI foundation have used Zinc Finger Proteins Transcriptions Factors (ZFP-TFs) to selectively targets mutant allele of the Huntington gene (HTT) and repress its expression 99% while retaining 86% of the normal allele.

Huntington is a fatal, progressive, neurodegenerative disorder caused by a dominant mutation involving the expansion of CAG trinucleotide repeat in exon 1 of the HTT gene. Fully penetrant disease alleles of mutant HTT have more than 39 CAG repeats, but most HD patients have one healthy wild-type copy of HTT with less than 22 CAG repeats. Sangamo scientist has developed ZFP-TFs which could bind only to the mutant allele avoiding the normal wild type and repressed its expression. Data from preclinical in vivo studies using different HD mouse models demonstrated improvements in a range of molecular, histopathological, electrophysiological, and other functional endpoints following treatment with Sangamo’s ZFP-TFs.

Finally, extensive in vivo tolerability assessments showed no evidence of a neuroinflammatory response or changes in behavior or locomotor function in mice treated with ZFP-TFs out to 15 months of age.

Sangamo's zinc finger protein transcription factor (ZFP-TFs) gene regulation technology:

IT is designed to either selectively repress (down-regulate) or activate (up-regulate) the expression of a specific gene or gene allele. Sangamo has a collaboration with Pfizer, deploying the ZFP-TF gene regulation approach to repress the expression of the mutated C9ORF72 gene allele linked to genetic forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Sangamo is also developing ZFP-TFs to down-regulate the expression of tau, a protein associated with Alzheimer's disease and other tauopathies.

About Huntington Disease:

Huntington’s disease (HD) is an inherited neurodegenerative disease that typically presents in adults aged between 30 and 50. HD is caused by a mutation in one of the alleles of the huntingtin gene (HTT), leaving only one functional or healthy copy of HTT in the cell. The mutated HTT produces the mutant HTT protein, leading to profound neuronal loss and progressive deterioration of motor, psychiatric, and cognitive abilities. There are currently no disease-modifying therapies available for HD.

Reference: Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington's disease. July Nature Medicine.

https://doi.org/10.1038/s41591-019-0478-3

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