LoQus23 moves Huntington’s disease candidate into development

Cambridge, England-based LoQus23 Therapeutics has nominated LQT-23 as its lead development candidate, advancing a novel small-molecule approach aimed at slowing or potentially halting the progression of Huntington’s disease, a rare and fatal inherited neurodegenerative disorder with currently no approved therapies.

LQT-23 targets MutSβ, a protein complex that has emerged as a central driver of disease progression in Huntington’s disease. Rather than focusing on downstream toxic proteins, the drug is designed to intervene earlier in the disease cascade by suppressing somatic expansion.

Targeting the root of disease progression

Huntington’s disease is caused by an abnormal expansion of CAG repeats in the huntingtin gene. While individuals inherit a pathogenic repeat length at birth, it is the continued expansion of these repeats in brain cells that ultimately triggers neurodegeneration, typically decades later. This process helps explain the delayed onset of symptoms and has increasingly become a focal point for therapeutic development.

Genetic, post-mortem and mechanistic studies have converged on MSH3, a key component of the MutSβ complex, as one of the most strongly validated targets in this pathway. However, MutSβ has long been considered difficult to modulate with small molecules due to its complex structure and biological role.

A small-molecule approach to a difficult target

LoQus23 says LQT-23 represents a significant advance, combining high potency with a novel allosteric mechanism designed to inhibit MutSβ activity. In preclinical studies, the compound demonstrated selective modulation of the target and robust suppression of somatic expansion in Huntington’s disease cellular systems and animal models.

The company plans to continue preclinical development through 2026 and is aiming to file regulatory submissions to initiate clinical testing later this year. Chief Executive Officer David Reynolds described the nomination of LQT-23 as a key milestone, reflecting years of work to build disease-relevant assays and identify compounds capable of engaging what he called “an exceptionally challenging target.”

Positioning in a crowded therapeutic landscape

The program enters a rapidly evolving field that includes gene therapies and antisense oligonucleotide approaches designed to lower huntingtin protein levels.

Several therapeutic leads for therapy aim to reduce the production of mutant huntingtin at the DNA or RNA level, either by delivering gene-editing or gene-silencing constructs to neurons using viral vectors or by administering antisense oligonucleotides that bind huntingtin mRNA and suppress its translation through repeated intrathecal dosing. While these strategies have shown biological activity, their development has been tempered by challenges related to brain-wide delivery, long-term safety, treatment burden and cost. Oral small molecules offer a potentially more flexible and scalable alternative, particularly for long-term treatment or preventive use in individuals who carry the mutant gene but have not yet developed symptoms.

Founded in 2019, LoQus23 focuses on developing oral small-molecule inhibitors of somatic expansion for Huntington’s disease and related disorders. The company raised £35 million in a Series A financing round in 2024, led by Forbion with participation from the Dementia Discovery Fund and Novartis Venture Fund.

For the estimated hundreds of thousands of patients affected worldwide (with up to 30.000 in the US alone), the growing diversity of therapeutic strategies offers cautious optimism that meaningful disease-modifying treatments may finally be within reach.