Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by motor neuron degeneration and resulting muscle wasting. The ~6,000 new cases of ALS in the US each year afflicts those >40 years of age. There is no effective treatment for ALS and those who contract the disease die 2-5 years after diagnosis. Most causes of ALS are unknown, but the most common known genetic cause is an aberrant C9ORF72 gene. Within this gene, a DNA GGGGCC hexanucleotide sequence is reiterated perhaps thousands of times, which causes the disease. This G4C2 expansion is transcribed into RNA that in turn generate dipeptide repeat proteins (DPRs), whose toxicity is thought to promote motor neuron degeneration. We have identified regions in C9ORF72 RNA that are the start sites for DPR synthesis. These start (ribosome initiation) sites can be occluded by binding to complementary DNA antisense oligonucleotides (AS-ODNs), which are modified to readily enter cells of the nervous system and stably and specifically bind their target sequences in C9ORF72 RNA. Such AS-ODNs would inhibit DPR production, thereby slowing or inhibiting disease progression. We propose to use human disease neurons in culture and C9ORF72 model mice to test the efficacy and specificity of AS-ODNs to inhibit DPR synthesis and mitigate ALS pathophysiology.

Public Health Relevance

One prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is a hexanucleotide repeat expansion in the gene C9ORF72. Polydipeptide repeat (DPR) proteins derived from this expansion are thought to be toxic and contribute to disease pathology. We propose a novel mechanism to inhibit DPR production, which may mitigate or slow progress of these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS109847-02
Application #
9770966
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Cheever, Thomas
Project Start
2018-09-01
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655