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An insight into allele-selective approaches to lowering mutant huntingtin protein for Huntington's disease treatment

Jia-Yuan Yao1, Ting Liu2, Xin-Ru Hu1

  • 1The First Clinical College, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, PR China.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|October 15, 2024
PubMed

Insights

Huntington's disease (HD) treatments are lacking. This review explores allele-selective therapies targeting mutant huntingtin (mHTT) DNA, RNA, or protein, offering a promising avenue for HD treatment research.

Area of Science:

  • Neurodegenerative Disorders
  • Genetics
  • Molecular Biology

Background:

  • Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT).
  • The expanded CAG repeat leads to a toxic gain-of-function of the mutant huntingtin protein (mHTT).
  • Currently, no effective therapies exist to halt HD progression.

Purpose of the Study:

  • To review therapeutic strategies for Huntington's disease that selectively target mutant huntingtin (mHTT).
  • To evaluate the preclinical and clinical outcomes of allele-selective mHTT lowering approaches.
  • To identify challenges and potential novel ideas for HD therapeutic research.

Main Methods:

  • Review of scientific literature on allele-selective therapies for Huntington's disease.
  • Analysis of approaches targeting mutant huntingtin gene (HTT) DNA, RNA, and protein.
  • Examination of preclinical and clinical data for emerging HD treatments.

Main Results:

  • Allele-selective lowering of mHTT expression presents a promising therapeutic strategy for HD.
  • Targeting mutant HTT DNA, RNA, or the mHTT protein itself are key approaches.
  • Several preclinical and clinical studies show potential but face challenges.

Conclusions:

  • Developing therapies that selectively reduce mHTT while preserving wild-type huntingtin protein (wtHTT) is crucial for HD treatment.
  • Allele-selective strategies offer a promising path forward for Huntington's disease therapeutics.
  • Further research is needed to overcome challenges and advance these novel HD treatments.

Keywords:
Allele-selective approachDNA-based approachHuntington's diseaseProtein-based approachRNA-based approach

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