Skip to content
Project Directory
  • Français
Donate Now
  • Français
  • About
    • What We Do
    • Leadership
    • Team
    • Publications
    • Careers
  • Diseases/Disorders
    • One Brain
    • ALS
    • Alzheimer’s
    • Autism
    • Brain Cancer
    • Brain Injury
    • Epilepsy
    • Mental Illness
    • Multiple Sclerosis
    • Parkinson’s
    • Stroke
    • Other
  • Research
    • Programs
    • Funding Opportunities
    • Program Partners
    • Announcements
  • Impact
  • Ways To Give
    • Giving to Research
    • How You Can Help
    • Events

Funded Grants

Back to results

Neuronal reprogramming as a novel therapeutic strategy to treat Amyotrophic lateral sclerosis

Project Overview

The demonstration that mature somatic cells can be converted to new, heterologous cell types, now termed “cellular reprogramming”, led to the 2012 Nobel Prize in Physiology or Medicine, and sparked an explosion of studies investigating the therapeutic potential of such an approach. Direct neuronal reprogramming refers to the conversion of any terminally differentiated cell to an induced (i) Neuron without traversing a pluripotent state. My goal is to examine the therapeutic potential of direct neuronal reprogramming to treat amyotrophic lateral sclerosis (ALS). Specifically, I aim to convert astrocytes in the motor cortex to inhibitory GABAergic neurons in a SOD1G93A mouse model of ALS. The rationale for my approach is that: (1) upper motor neuron pathology in the motor cortex precedes lower motor neuron loss in the brainstem and spinal cord in ALS animal models and patients. Moreover, there is growing support for the idea that interventions targeting the motor cortex can have therapeutic benefits. (2) GABAergic neurons are hypoactive in the SOD1G93A motor cortex, and their activation preserves motor function in SOD1G93A mice. To optimize our approach, we have used our knowledge of embryonic neurogenesis to create phosphosite mutations in Ascl1, a basic-helix-loop-helix bHLH transcription factor that promotes the differentiation of GABAergic neurons. The serine (S) to alanine (A) mutations were made in residues adjacent to prolines (P), creating SA-mutations that keep Ascl1 active even in the presence of inhibitory proline-directed serine-threonine kinases (e.g., ERK, GSK3, CDKs). Using adeno-associated virus (AAV) gene delivery to the motor cortex, I showed that Ascl1 carrying six SA mutations (Ascl1-SA6) is more efficient at inducing neuronal conversion of adult brain astrocytes than native Ascl1. I also have preliminary evidence that Ascl1-SA6 expression in motor cortex astrocytes delays the onset of motor deficits in SOD1G93A mice. I hypothesize that mutated Ascl1 will convert motor cortex astrocytes to GABAergic iNeurons that will integrate into neural circuits to delay ALS progression. I test this hypothesis in three aims:

Aim 1. To confirm glial origins and functional properties of iNeurons in vivo

Aim 2. Assess Ascl1-SA6 reprogramming effects on brain health (cell autonomous & non-cell autonomous).

Aim 3. Assess Ascl1-SA6 reprogramming in a human cerebral organoid (CO) model of ALS.

Impact: Neuronal reprogramming is an innovative way to replace lost neurons. I will uncover new mechanistic insights into how optimized Ascl1 improves brain health in rodent models in vivo and in a human model of ALS.

Principal Investigator

Hussein Ghazale , Sunnybrook Research Institute

Partners and Donors

ALS Society of Canada

Fondation Vincent Bourque

Project Ongoing

Neuronal reprogramming as a novel therapeutic strategy to treat Amyotrophic lateral sclerosis

  • Program Type

    Capacity building grants

  • Area of research

    Neurodegeneration

  • Competition

    ALS Canada-Brain Canada Trainee Program 2022

  • Province

    Ontario

  • Start Date

    2022

  • Total Grant Amount

    $165,000

  • Health Canada Contribution

    $82,500

Contact Us

1200 McGill College Avenue
Suite 1600, Montreal, Quebec
H3B 4G7

+1 (514) 989-2989 info@braincanada.ca

Playing with Marbles Podcast

Join us and take a journey to the real last great frontier – the brain.

Listen

Subscribe to Brain News

Receive our monthly electronic newsletter with updates on funded projects, upcoming events and breakthroughs in brain research.

Sign Up

Territorial acknowledgement

The offices of Brain Canada Foundation are located on the traditional, ancestral territory of the Kanien'kehá:ka Peoples, a place which has long served as a site of meeting and exchange amongst nations. We honour and pay respect to elders past, present and emerging, and dedicate ourselves to moving forward in the spirit of partnership, collaboration, and reconciliation. In our work, we focus our efforts on the Truth and Reconciliation Commission’s Calls to Action, particularly those that pertain to improving health for Indigenous Peoples and that focus on advancing our own learning on Indigenous issues.

© 2023 Brain Canada Foundation

Registration number: 89105 2094 RR0001

  • Terms and Conditions
  • Privacy Policy

Design by Field Trip & Co