Role of ataxin-3 polyadenylation site selection in ALS neuron toxicity and disease pathogenesis

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Grant Award Details

Grant Number:
DISC0-14448
Investigator(s):
Human Stem Cell Use:
Cell Line Generation:
Award Value:
$1,514,416
Status:
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.