ANTISENSE OLIGONUCLEOTIDE THERAPY FOR HUNTINGTON’S DISEASE

Summary

Leiden University Medical Center's NeuroD research group has developed an antisense oligonucleotide (ASO) therapy for Huntington's Disease (HD), targeting the disease-causing HTT transcript. This novel therapy aims to reduce the toxicity of mutant HTT protein while preserving the vital functions of the normal protein, and has demonstrated improvement in symptoms in an HD mouse model, marking a significant advance in HD treatment.

Background

HD is a rare neurodegenerative genetic disorder caused by an abnormal expansion of a CAG triplet repeat in the HTT gene. This results in a mutant huntington protein causing the disease. Current approved treatments focus on symptoms rather than the underlying genetic cause. Proteolytic cleavage of the full length protein into smaller and more toxic N-terminal fragments are an important step in HD pathology. Targeting these cleavage sites in HTT RNA directly offers a promising path for altering the disease course, considering the essential roles of the normal huntington protein.

Technology

Our ASO therapy involves splice modulation of HTT pre-mRNA, employing a strategy that targets exon 12 of both the wild-type and mutant HTT. This approach creates a caspase-6 resistant HTT protein (Htt∆12), reducing the toxicity of the mutant protein. This method importantly preserves enough HTT function, crucial for brain health and homeostasis, as complete silencing of HTT can affect motor function, anxiety behavior, and survival.

Research and Development

Extensive preclinical studies conducted in YAC128 Huntington mice have demonstrated the efficacy of the ASO therapy. Key findings include:

• Improved phenotypes: treated mice exhibited significant improvements in body weight, activity levels, and reduced loss of striatal volume
• Gene expression and protein level changes: post-treatment analyses revealed a trend toward normalization of striatal gene expression and protein levels, moving closer to wild-type levels

Value proposition

Our ASO therapy for HD offers a transformative treatment option with potential benefits including:

• Targeted Genetic Therapy: direct targeting of the HTT gene mutation, offering a more effective treatment strategy compared to current symptomatic treatments.
• Preservation of Normal HTT Function: unique exon skipping approach that maintains essential HTT functions, crucial for brain health.
• Strong Preclinical Efficacy: demonstrated functional efficacy in animal models, setting a solid foundation for human clinical trials.

Market opportunity

The Huntington’s disease is a rare disease with prevalence of 7-8 per 100,000 in Europe and North America. There are currently no treatments available that slow or reverse the disease. The HD treatment market is projected to expand significantly, from USD 380 million in 2022 to an estimated USD 2018 million by 2030, at a CAGR of 23.20% (Grand View Research).

Team

The development of this therapy is led by Prof. Dr. Willeke van Roon-Mom and her team at the NeuroD research group in the LUMC. The team combines expertise in molecular neuroscience, genetic therapies, and clinical neurology, ensuring a comprehensive and innovative approach to HD treatment. There are strong links to the Neurology department at the LUMC where dr. Susanne de Bots leads the largest outpatient clinic of the Netherlands with around 500 HD patient visits per year.