Huntington's disease: Molecular basis of pathology and status of current therapeutic approaches

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is a hereditary neurodegenerative disorder impacting motor and cognitive functions.
• It stems from mutations in the huntingtin (HTT) gene, leading to toxic expanded polyglutamine (polyQ) tracts in the huntingtin protein (mutHTT).
• Current treatments offer only symptomatic relief, lacking a cure.

Purpose of the Study:

• To review current and emerging therapeutic strategies for Huntington's disease.
• To highlight the molecular basis of HD and its impact on specific neuronal populations.
• To discuss the potential of both pharmacological and regenerative medicine approaches.

Main Methods:

• Review of preclinical and clinical research on HD therapeutics.
• Analysis of strategies targeting mutHTT reduction at transcriptional and translational levels.
• Exploration of proteasomal degradation and post-translational modification of mutHTT.
• Assessment of stem cell therapy, including induced pluripotent stem cells (iPSCs).

Main Results:

• Multiple therapeutic avenues are under investigation, including gene silencing (RNA interference, antisense oligonucleotides) and protein degradation.
• Targeting mutHTT at various molecular levels shows promise in preclinical models.
• Stem cell therapy, particularly using patient-derived iPSCs, is being explored for neuronal replacement.
• Post-translational modification of mutHTT is an emerging area for drug development.

Conclusions:

• No cure currently exists for HD, but diverse therapeutic strategies are advancing.
• Reducing toxic mutHTT protein and replacing lost neurons are key therapeutic goals.
• Ongoing clinical investigations offer hope for improved treatments and quality of life for HD patients.