Huntington's Disease and other triplet expansion disorders – targeting the root cause of progression
About Huntington’s Disease – a fatal disorder with no effective treatment
Huntington’s Disease (HD) is a devastating, inherited neurodegenerative disorder that causes progressive, irreversible brain deterioration. Symptoms typically emerge between ages 30 and 50 and include movement disorders, cognitive decline, and psychiatric symptoms. There is currently no approved disease-modifying treatment, and affected individuals typically die within 15 years of symptom onset. An estimated 10–12 per 100,000 people are affected, with a similar number at risk or asymptomatic carriers.
A shift in the HD paradigm
HD is caused by progressive somatic expansion of CAG trinucleotide repeats in the HTT gene. As these repeats extend in length over time, they trigger a cascade of toxicity at the DNA, RNA, and protein levels, ultimately leading to neuronal dysfunction and death.
Historically, therapeutic strategies have focused on reducing mutant Huntingtin protein (mHTT) – the toxic protein product of the expanded allele. However, these efforts have faced challenges with both safety and efficacy, and emerging evidence suggests that targeting mHTT alone is insufficient to halt disease progression.
Recent landmark research (e.g., Cell, Nature Medicine) has demonstrated that slowing or halting the CAG expansion process itself, before repeats reach a critical threshold in too many neurons, offers the most promising opportunity to delay disease onset and progression. Effective treatment will require early, upstream intervention targeting the underlying genetic driver, alongside approaches to address downstream effects.
Harness’ approach: Controlled FAN1 upregulation for disease modification
Harness’ lead program has the potential to be a first and best-in-class disease-modifying therapy. It directly targets the underlying driver of HD: CAG repeat expansion. Our novel approach centers on FAN1, a DNA repair nuclease with the strongest genetic association to disease onset.
Why FAN1?
- FAN1 is a key suppressor of somatic expansion, shown to slow CAG repeat growth in multiple independent studies
- Genome-wide association studies (GWAS) and SNP data demonstrate that natural variation in FAN1 levels correlates with delayed disease onset
- Experimental validation in patient-derived neuronal models shows that modest, controlled increases in FAN1 can safely and effectively slow the expansion process
Whilst FAN1 has been a priority target since the publication of the GWAS studies in 2019, it was up till now considered undruggable, as traditional upregulation methods risked harmful overexpression or lacked specificity.
Harness is the first to overcome this challenge.
Our therapeutic solution
- A first-in-class, ASO-based therapy designed to precisely and safely upregulate FAN1 at the post-transcriptional level.
- Built on our proprietary MISBA™ platform, the ASO construct:
- Provides self-limiting, controlled increases in FAN1 levels within a safe and efficacious range to avoid the risks associated with over-expression
- Is delivered directly into the CNS using established surgical techniques, reducing systemic exposure and mitigating oncogenic risk
- Uses clinically validated ASO chemistries to reduce developability risks
- Preclinical studies show that this approach slows somatic expansion in disease-relevant neuronal models
Beyond Huntington’s
FAN1’s role in triplet repeat expansion suppression extends beyond HD. This opens the door to future applications in other expansion-driven diseases, including:
- Spinocerebellar ataxias
- Fragile X-associated disorders
- Myotonic dystrophy type 1 (DM1)
Please contact us for further information about our Huntington's Disease Programme.