information: Publication of results in a medical journal
Announcement: publication of results in Nature Medicine
Company: Sangamo Therapeutics (USA - CA)
Product: allele-selective zinc finger protein transcription-factors (ZFP-TFs)
mechanism: gene editing/gene therapy
Disease: Huntington's disease
area: Rare diseases - Neurodegenerative diseases
- • On July 1, 2019, Sangamo Therapeutics announced the publication of a manuscript describing the activity of allele-selective zinc finger protein transcription-factors (ZFP-TFs) in preclinical models of Huntington’s disease (HD). The publication describes research by Sangamo and collaborators at the CHDI Foundation, in which ZFP-TFs were engineered to selectively target the mutant form of the huntingtin gene (HTT) and repress its transcription, selectively lowering production of the mutant Huntingtin protein (mHTT). Preclinical data from HD patient-derived fibroblasts and neurons demonstrated that a single administration of ZFP-TFs resulted in the selective repression of over 99% of HD-causing HTT disease alleles over a wide dose range, while preserving the expression of at least 86% of healthy wild-type HTT alleles.
- Huntington’s disease is a progressive, fatal, neurodegenerative disorder caused by a dominant mutation involving the expansion of a 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. Led by first author Bryan Zeitler, PhD, Sangamo scientists engineered ZFP-TFs capable of preferentially binding longer CAG repeat arrays on the disease allele while avoiding the shorter repeat array on the healthy allele. These ZFP-TFs exhibited disease-allele selectivity and also demonstrated a high level of specificity for the mutant HTT repeat as compared to other CAG-containing genes in the human genome.
- 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. In neurons cultured from the zQ175 mouse model (~188 CAG repeats) of HD, recombinant AAV delivery of ZFP-TFs to primary neurons resulted in reduction of mutant HTT mRNA and HTT protein by more than 98% with no reduction of wild-type HTT. In vivo, toxic aggregates of the mutant HTT protein were reduced by greater than 99%. Moreover, the well-characterized zQ175 electrophysiological deficits in the brain were fully reversed following ZFP treatment. Functional restoration of neuronal biomarkers was also demonstrated by several measures, including the use of PET imaging ligands in living mice. This outcome has the potential to be translated for use as an efficacy marker in clinical trials. The results were confirmed and extended in an additional mouse model of HD, in which treatment with ZFP-TFs led to the repression of mutant HTT protein and significant improvement in motor function.
- 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. This suggests that the long-term striatal expression of ZFP-TFs is generally well-tolerated in mice.