Grant Award Details

Role of ataxin-3 polyadenylation site selection in ALS neuron toxicity and disease pathogenesis
Grant Type: 
Grant Number: 
DISC0-14448
Project Objective: 
  • This project will determine the functional significance of alternative polyadenylation (APA) of ATXN3 gene in ALS disease pathogenesis using IPSC-motor neurons and IPSC- cortical neurons, assess if reduced ATXN3 expression enhances ALS neurotoxicity, test if antisense oligonucleotides can reduce distal polyadenylation of ATXN3 to rescue ALS disease phenotypes in iPSC-derived neurons.
Investigator: 
Name: 
Institution: 
Type: 
PI
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Award Value: 
$1,514,416
Status: 
Pre-Active

Grant Application Details

Application Title: 
  • Role of ataxin-3 polyadenylation site selection in ALS neuron toxicity and disease pathogenesis
Public Abstract: 

Research Objective

Here we will study the role of ataxin-3 alternative polyadenylation in the pathogenesis of ALS, and test if ASOs can reduce distal polyadenylation of ataxin-3 to rescue ALS disease phenotypes

Impact

Our goal is to determine if ataxin-3 genetic dysregulation is a target for the development of therapies to treat ALS (Lou Gehrig's disease), frontotemporal dementia, and Alzheimer's disease

Major Proposed Activities

  • Assay ataxin-3 expression and function in motor neurons + cortical neurons derived from human stem cells for 3 ALS patients (who display a high-risk genetic alteration in ataxin-3) and 3 controls
  • Pinpoint the genetic alterations in the ataxin-3 gene most likely to account for high risk of developing ALS
  • Genetically modify a control human stem cell line to convert it to a high-risk ALS version by introducing the ataxin-3 genetic alteration
  • Assay ataxin-3 expression and function in motor neurons + cortical neurons derived from the genetically modified control line created in Activity 3 in comparison to its control (isogenic) counterpart
  • Develop a genetic therapy known as antisense oligonucleotides (ASOs) in human stem cells that is capable of reversing the effect of the ALS disease-causing genetic alteration in the ataxin-3 gene
  • Test if the most potent ASOs identified in Activity 5 can counter the ALS genetic risk factor in the ataxin-3 gene and thereby prevent ALS disease phenotypes in human stem cell-derived neurons
Statement of Benefit to California: 

There are no highly effective therapies to treat ALS and a closely related disorder known as frontotemporal dementia (FTD), where patients show aggregation of TDP-43 protein. Here we will study if a genetic alteration in a specific gene predisposes individuals to developing TDP-43 protein abnormalities, which are a central feature of ALS, FTD, and Alzheimer's disease, and will determine if a genetic therapy directed at this defect could hold promise as a therapy for these devastating disorders.

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