Prevent the progression of Huntington's Disease

Huntington's Disease (HD) is a triplet repeat disorder with high unmet need and disease burden. It is the most frequent autosomal dominant neurodegenerative disorder affecting ~12 in 100,000 (40,000 in US alone) with twice as many people with HD who are asymptomatic. HD causes irreversible deterioration in a person’s physical, mental, and emotional abilities, usually leading to premature death over 14-15 years. The onset is typically between 30 and 50 years old but can be younger. There are no disease modifying treatments currently licenced or in late phase, and delaying onset and slowing disease progression is the key objective for people with HD, their families and physicians.

Disease onset is driven by CAG triplet repeat expansion in the HTT gene encoding huntingtin protein (HTT). Age of onset is determined both by ‘inherited length’ and somatic expansion over the patient’s lifetime. The field has focused on selectively reducing mutant HTT protein, or total HTT protein but there are challenges with safety and efficacy including: drug specificity for HTT and the HTT1A splice variant; selecting the best route of administration for optimal biodistribution and safety profile; and the timing of intervention in the course of disease. More recent work points to disease onset being driven by genetic CAG repeat expansion, which is upstream of toxicity of mutant HTT protein.

CAG repeat expansion drives disease onset

Slowing or halting somatic expansion in early/prodromal patients could provide an opportunity for true disease modification.

Our approach has the potential to be a first and best-in-class disease-modifying therapy

SNP data and in vitro experimental data provides strong rationale for physiological upregulation of FAN1 to reduce, or even halt, the triplet expansion that drives Huntington’s disease progression.

The DNA damage repair pathway is the area of growing focus in the HD field given its potential to slow or halt the CAG expansion process, and so address all disease pathologies. The goal is to rebalance the pathway to prevent the creation of further CAG repeats. GWAS studies link multiple genes in this pathway to disease onset but only those relevant to knockdown are currently being prosecuted for therapeutic development. Our lead target, FAN1, has the strongest validation of all targets in this pathway with GWAS and +/- SNP data providing a clear link to disease onset. Experimental data in human/IPSC-neuronal models shows that modest target upregulation can slow CAG expansion with no apparent safety risk arising from controlled upregulation. Upregulation of FAN1 could reduce or halt CAG expansion, offering potential for delayed disease onset and reduced rate of disease progression.

Please contact us for further information about our Huntington's Disease Programme.

Our vision

Building the leading platform for physiological upregulation of neurodegenerative disease targets to enable truly disease-modifying therapies.

Our approach

Deep expertise & unique capabilities in RNA biology & neurodegeneration

High value targets

Ready to scale

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