An Agora Open Science Initiative

Targeting the underlying cause of Huntington’s disease

M4HD is exploring precision medicines that act directly on the HTT protein, the protein linked to the underlying cause of Huntington’s disease. 

The opportunity

A different starting point for drug discovery

Huntington’s disease (HD) is an inherited condition caused by a change in a single gene: huntingtin, or HTT. This genetic change produces an altered form of the HTT protein that damages brain cells over time.

Available treatments can help manage some symptoms of Huntington’s disease, but they do not address its underlying cause.

M4HD—Medicines for Huntington’s Disease—is an Agora Open Science Trust initiative created to explore a new way forward: developing precision medicines that act directly on the HTT protein.

Our researchers are working to identify small molecules that can bind to HTT precisely. These molecules could become starting points for medicines designed to reduce the amount or harmful effects of altered HTT in cells.

This is early-stage research. Considerable scientific work and testing will be required to determine whether this approach can lead to a safe and effective treatment. By building the tools, knowledge and chemical starting points needed to study HTT in new ways, M4HD aims to expand what may be possible in Huntington’s disease drug discovery.

A coordinated discovery platform

How M4HD works

M4HD combines expertise across structural biology, chemical biology, medicinal chemistry, artificial intelligence and Huntington's disease biology to develop medicines that directly target HTT.

Our integrated discovery platform spans the entire early drug discovery pipeline, from identifying druggable sites on HTT, to designing ligands, engineering degraders and evaluating therapeutic candidates in disease-relevant models.

  • Using structure-guided drug discovery, computational chemistry and biophysical screening to develop small molecules that bind HTT with high affinity and selectivity.

  • Transforming HTT ligands into PROTACs, molecular glues and other induced-proximity therapeutics that selectively remove disease-causing HTT from cells.

  • Determining high-resolution structures of HTT and HTT-ligand complexes to reveal new druggable pockets and guide rational drug design.

  • Applying machine learning, molecular simulation and physics-based computational methods to accelerate ligand discovery, optimisation and degrader design.

  • Developing chemical probes and mechanistic tools to understand HTT biology, validate therapeutic hypotheses and uncover new opportunities for intervention.

  • Testing candidate therapeutics in cellular and preclinical models of Huntington's disease to understand their effects on HTT biology and disease progression.

Open science, shared progress

Built to help knowledge move.

M4HD was created by Agora Open Science Trust, a Canadian charity working to advance the discovery and development of affordable medicines through open science.

Complex diseases cannot be solved by one laboratory or discipline alone. M4HD is designed to bring researchers together, share knowledge and enable different teams to build on one another’s work.It brings together expertise in structural biology, computational drug discovery, medicinal chemistry, chemical biology and Huntington’s disease research.

Information and support

M4HD is a drug discovery research initiative and does not provide medical advice, clinical services or individual guidance about Huntington’s disease.

For accessible news and explanations about HD research, visit HDBuzz.

For information, educational materials and support resources, visit the Huntington Society of Canada or the Huntington’s Disease Foundation.