Small molecule splicing modifiers with systemic HTT-lowering activity

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Huntington's disease (HD) is an inherited neurodegenerative disorder caused by expanded CAG trinucleotide repeats in the huntingtin (HTT) gene.
• Mutant HTT protein's toxic gain-of-function drives HD pathogenesis, with animal models showing reduced HTT levels alleviate symptoms.
• Current investigational drugs for HD require invasive delivery to the central nervous system (CNS) and lack broad CNS distribution.

Purpose of the Study:

• To identify orally bioavailable small molecules for reducing huntingtin (HTT) protein levels.
• To achieve broad distribution of therapeutic agents throughout the CNS.
• To develop a novel therapeutic strategy for Huntington's disease (HD) by modulating HTT expression.

Main Methods:

• Identification of orally bioavailable small molecules.
• Assessment of CNS and peripheral distribution of these molecules.
• Analysis of HTT expression levels following treatment.
• Investigation of the mechanism involving selective modulation of pre-messenger RNA splicing, specifically promoting stop-codon pseudoexon inclusion.

Main Results:

• Discovery of orally bioavailable small molecules demonstrating broad CNS distribution.
• Consistent reduction of HTT expression in both the CNS and periphery.
• Mechanism confirmed: compounds promote stop-codon pseudoexon inclusion, leading to HTT mRNA degradation.

Conclusions:

• Orally bioavailable small molecules can effectively lower HTT expression throughout the CNS and periphery.
• Targeting pre-messenger RNA splicing represents a novel and promising therapeutic approach for Huntington's disease (HD).
• This strategy offers potential for improved treatment delivery and efficacy compared to existing investigational drugs.