Science

We are developing small molecule drugs that could stop the pathogenic triplet expansion that is the cause and driver of Huntington’s Disease, myotonic dystrophy type 1, and other triplet repeat expansion diseases.

Huntington’s disease is an autosomal dominant neurodegenerative disorder for which there is currently no disease modifying treatment available and which currently has 30,000 patients in the US alone.

It has long been known that the mutation Huntington’s patients inherit is a longer tract of the repetitive CAG nucleotide sequence in their Huntingtin gene. Healthy people have up to 36 repeats, whereas individuals with 40 or more repeats will go on to develop the disease.

There’s now an overwhelming body of evidence from both genetic studies with Huntington’s patients and academic mechanistic studies that shows it is not the CAG repeat you inherit at conception that causes neurodegeneration, but rather its further expansion up to hundreds of repeats during your lifetime. You can read some of these papers here.

Primary disease driver – somatic expansion within the huntingtin gene

The first stage of the disease is where the CAG tract expands in vulnerable neurones through a slow process over several decades known as somatic expansion, which is mediated by aberrant DNA mismatch repair.

Secondary toxicity – toxic huntingtin protein causes neurodegeneration

The second stage is triggered above an expansion threshold where the resulting huntingtin protein becomes toxic and leads to neuronal dysfunction and ultimately cell death. The neurodegeneration in the vulnerable brain regions produces the characteristic, slowly progressing, symptoms of the disease.

The discovery that aberrant DNA mismatch repair is the key process in Huntington’s disease and other triplet repeat diseases has revolutionised drug discovery thinking.

Drug target

Superb mechanistic and genetic evidence points to the MutSβ heterodimer protein, which is the first step of the mismatch repair pathway, as being the best drug target for blocking somatic expansion and treating Huntington’s disease.

Our approach

The expert team at LoQus23 is taking a structure-based approach to develop small molecule drugs, which can offer more convenient administration than other approaches. Oral small molecule drugs have a strong track record in treating complex brain diseases and provide greater convenience for patients compared with other advanced treatment modalities.

We are identifying small molecule allosteric inhibitors of MutSβ to stop DNA instability and therefore slow neurodegeneration in Huntington’s disease and other triplet repeat expansion diseases. LoQus23’s lead programme, a potent allosteric small molecule MSH3 inhibitor, part of the MutSβ complex, will enter the clinic in 2026.