FINGERS4CURE - Activity of Huntington's disease gene curbed for six months in mice
Huntington’s disease (HD) is a lethal brain wasting disease that has no cure and affects about 700,000 people worldwide. People living with HD have inherited one copy of a 'bad' gene that causes sticky protein aggregates in the brain. Symptoms typically develop at 35 - 45 years of age, although they can start much earlier. We have spent the last ten years developing a genetic off-switch, called a zinc finger, that specifically targets the bad mutant Huntingtin gene. The zinc finger sticks to DNA and switches off the bad gene. Back in 2012, we were the first to show that we could deliver the zinc fingers to mice quite efficiently and that we could specifically turn off the mutant gene. Excitingly, one injection halted neurological symptoms in Huntington's mice for a couple of weeks. The problem at that stage was that the zinc finger effect did not last very long. The new FINGERS4CURE project aimed to overcome that problem and get the project ready for an industrial partner to take to clinical trials.
We used the FINGERS4CURE project to optimise the specific design of our zinc finger to make it invisible to the host immune system, and to allow its expression for a much longer period of time. We have just published a new paper on this work, reporting how we can now achieve specific repression of mutant Huntingtin for a least 6 months after a single injection. For comparison, other therapeutic strategies, such as antisense oligonucleotides or siRNAs, act one level up from the DNA - at the level of RNA - and require more frequent infusions. Our long-term repression, which works at the root of expression, is a major step forward and required a lot of trial-and-error work.
Simultaneously, the project has worked on translating the project to industry by strengthening the patent portfolio of the project and contacting potential partners. The technology transfer teams of Imperial College London and the Centre for Genomic Regulation in Barcelona (whose institutes co-hosted this ERC work) have worked together on a new joint patent, while contacting investors and industry partners to develop a clinical pipeline. The work has also received 1-year follow-on funding from the Imperial Confidence-in-Concept Scheme (August 2016), which will support the next steps towards translation.
Accompanying paper:
Deimmunization for gene therapy: hostmatching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice' by Carmen Agustín-Pavón, Michal Mielcarek, Mireia Garriga-Canut and Mark Isalan is published in Molecular Neurodegeneration 11:64, 2016.
In the News:
http://www.huffingtonpost.co.uk/entry/a-single-injection-of-a-new-treatment-has-halted-progress-of-huntingdons-disease-for-months_uk_57d69301e4b0d45ff8726d24(opens in new window)http://www.crg.eu/sites/default/files/crg_media/160901_EuropeResearchResultsMagazine_MIsalan.pdf(opens in new window)
