Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of...

Area of Science:

• Genetics and Molecular Biology
• Neurodegenerative Diseases
• Drug Discovery and Development

Background:

• Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin (HTT) gene.
• Current therapeutic strategies for HD are limited, highlighting the need for novel approaches to reduce the levels of toxic mutant huntingtin (mHTT) protein.

Purpose of the Study:

• To design and optimize novel huntingtin (HTT) pre-mRNA splicing modulators.
• To promote the insertion of a pseudoexon containing a premature termination codon, leading to nonsense-mediated decay of HTT mRNA.
• To develop a potent, CNS-penetrant, and orally bioavailable compound for reducing HTT protein levels.

Main Methods:

• Chemical modification of a benzamide core to a pyrazine amide structure.
• Optimization of HTT pre-mRNA splicing modulators for potency, CNS penetration, and oral bioavailability.
• Evaluation of compound 27 in human HD stem cells and mouse BACHD models to assess HTT-lowering efficacy.

Main Results:

• A potent HTT-splicing modulator, compound 27, was successfully designed and optimized.
• Compound 27 demonstrated reduction in canonical splicing of HTT RNA at the exon 49-50 junction.
• Significant reduction in HTT protein levels was observed in both human HD stem cells and mouse BACHD models.

Conclusions:

• Compound 27 represents a structurally diverse and effective HTT-splicing modulator.
• This compound has the potential to reduce toxic mHTT protein levels, offering a new therapeutic avenue for Huntington's disease.
• Compound 27 may aid in understanding the mechanisms underlying adverse effects like peripheral neuropathy associated with other splicing modulators, such as branaplam.