Towards a treatment for Machado-Joseph disease, a rare inherited neurodegenerative disorder

Patrícia Maciel

Life and Health Sciences Research Institute (ICVS), Braga, Portugal

Machado-Joseph disease is a rare inherited neurodegenerative disorder that affects one or two cases per 100,000 population and primarily causes symptoms such as poor coordination of movements, unsteady gait (ataxia), weakness in arms and legs and difficulty with speech and swallowing. It is caused by mutation of a protein called ataxin-3, which tends to aggregate, leading to toxic effects on neurons and resulting in their progressive dysfunction and disappearance.

There is still no effective treatment to slow or cure the disease, which causes a gradual loss of autonomy for those affected, eventually confining them to a wheelchair or bed. A drug capable of delaying the onset and progression of the disease would have a significant health, social and economic impact.

In addition to gene therapies aimed at silencing the expression of the mutant gene, which are currently being tested and face several major challenges related to safety and effective delivery of the therapy to the affected regions of the brain, other therapies are being explored based on the administration of small molecules capable of inducing protein degradation. In this regard, this project will work with small bifunctional molecules that bind to both the mutated protein and to the cellular machinery responsible for degrading and eliminating proteins. The goal is to develop these small molecules as a promising alternative to gene therapy to selectively eliminate the mutated proteins that cause this disorder in nerve cells.

• Fernanda Borges, Chemistry Research Centre of the University of Porto (CIQUP), Portugal

New molecules harnessing targeted protein degradation for the treatment of Machado-Joseph disease

€999,026.16

*Award-winning project in collaboration with the Fundação para a Ciência e a Tecnologia