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Updated: Mar 23, 2026

Evaluation of Exon Inclusion Induced by Splice Switching Antisense Oligonucleotides in SMA Patient Fibroblasts
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Discovery and Optimization of Thienopyrazine RNA-Splicing Modulators for the Treatment of Huntington's Disease

Chaofan Xu1, Neeta Abraham2, Nupur Bansal1

  • 1Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.

Journal of Medicinal Chemistry
|March 17, 2026
PubMed

Insights

Researchers discovered new splicing modulators for Huntington's disease (HD). These compounds lower levels of mutant Huntington protein (mHTT) by promoting a stop codon, offering a potential new treatment strategy for HD.

Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Huntington's disease (HD) is a progressive neurodegenerative disorder.
  • It is caused by a CAG-repeat expansion in the Huntington gene (HTT).
  • Current treatments are limited, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To discover novel small molecules that modulate HTT pre-mRNA splicing.
  • To identify compounds that promote the inclusion of a cryptic stop codon, reducing mutant Huntington protein (mHTT) levels.
  • To develop a potent, selective, and orally bioavailable HTT-splicing modulator for HD.

Main Methods:

  • Medicinal chemistry optimization of a thienopyridine amide core.
  • In vitro splicing assays using human cells.
  • In vivo studies in mouse YAC128 models of HD.
  • Off-target profiling using RASL- and RNA-seq analysis.

Main Results:

  • Discovery of a series of HTT pre-mRNA-splicing modulators.
  • Identification of BIO-6553, a potent, CNS-penetrant, selective, and orally bioavailable compound.
  • Demonstrated significant HTT-lowering in human cells and mouse models.
  • BIO-6553 exhibits an attractive off-target profile.

Conclusions:

  • BIO-6553 is a structurally distinct and promising HTT-splicing modulator.
  • This compound represents a potential therapeutic candidate for Huntington's disease.
  • The developed compounds offer a novel approach to lower mHTT levels in HD.

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