Related Experiment Video

Updated: May 8, 2025

Direct Intraventricular Delivery of Drugs to the Rodent Central Nervous System
14:55

Direct Intraventricular Delivery of Drugs to the Rodent Central Nervous System

Published on: May 12, 2013

60.0K

Interventionally targeting somatic CAG expansions can be a rapid disease-modifying therapeutic avenue: Preclinical

Terence Gall-Duncan1,2, Sangyoon Y Ko3, Isabelle K Quick1,2

  • 1Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.

Biorxiv : the Preprint Server for Biology
|May 7, 2025
PubMed

Insights

Targeting somatic CAG expansions in Huntington disease (HD) mice rapidly improved motor function and molecular hallmarks. This approach offers a promising therapeutic avenue for HD and other repeat expansion disorders.

Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Huntington disease (HD) is a neurodegenerative disorder caused by inherited CAG repeat expansions.
  • These CAG repeats expand somatically in the brain, accelerating disease progression.
  • The therapeutic potential of reducing somatic CAG expansions in HD remains largely unexplored.

Purpose of the Study:

  • To investigate whether intervening in somatic CAG expansion can modify clinical phenotypes in a mouse model of HD.
  • To determine the therapeutic window and specific phenotypes affected by somatic expansion modulation.
  • To assess the potential of blood biomarkers for target engagement and efficacy.

Main Methods:

  • Acute administration of a naphthyridine-azaquinolone ligand to contract CAG repeats in young (CAG)120 HD mice.
  • Evaluation of motor function, including locomotion, balance, coordination, and muscle strength.
  • Analysis of molecular disease markers: mHTT aggregates, nuclear envelope morphology, nucleocytoplasmic mRNA transport, transcriptomic changes, neuroinflammation, and neurodegeneration.
  • Assessment of effects in muscle and blood, including CAG instability and neurofilament light levels.

Main Results:

  • The treatment induced CAG contractions across brain regions.
  • Significant improvements were observed in motor functions and molecular disease landmarks.
  • Beneficial effects extended to muscle and blood, with blood CAG instability correlating with brain instability.
  • Diminished neurofilament light levels in blood serum indicated reduced neurodegeneration.

Conclusions:

  • Targeting somatic repeat expansions is a rapid, disease-modifying therapeutic strategy for Huntington disease.
  • This approach may also be applicable to other repeat expansion diseases.
  • The findings support an interconnected etiologic pathway involving somatic CAG expansions, informing future clinical trial designs.

More Related Videos

A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations08:22

A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations

Published on: December 1, 2017

8.5K
In Vivo Modeling of the Morbid Human Genome using Danio rerio12:31

In Vivo Modeling of the Morbid Human Genome using Danio rerio

Published on: August 24, 2013

20.6K

Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.4K
Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
397
Gene Therapy00:59

Gene Therapy

Gene therapy is a technique where a gene is inserted into a person’s cells to prevent or treat a serious disease. The added gene may be a healthy version of the gene that is mutated in the patient, or it could be a different gene that inactivates or compensates for the patient’s disease-causing gene. For example, in patients with severe combined immunodeficiency (SCID) due to a mutation in the gene for the enzyme adenosine deaminase, a functioning version of the gene can be...
24.9K