Researchers at the Stanford University School of Medicine in the US have identified potential drug targets for amyotrophic lateral sclerosis (ALS) using CRISPR-Cas9 genome editing technology.
ALS is a neurodegenerative disease characterised by abnormal protein build up caused by C9orf72 gene mutations that lead to blocked neuronal function and cell death.
In an effort to understand disease progression, the researchers identified various genes that helped neurons defend against toxic protein.
Genetics professor at the Stanford University School of Medicine Aaron Gitler said: “These toxic protein aggregates are what’s likely driving the pathology in the disease, but no one really knows how they cause neuronal cell death. That’s really what we wanted to probe in this study.”
The team used a genomewide screening approach that uses CRISPR-Cas9 to alter the function of every single human gene simultaneously. They used the technology to produce ‘gene knockouts’ that target genes with a kind of molecular scissors that makes accurate cuts, rendering the genes unable to function normally.
These gene knockouts were found to be helpful in identifying genes that either increase or prevent toxicity, meaning they can be used in the detection of specific genes involved in protecting neurons from degeneration.
According to researchers, the particular genes could also be possible targets for drug candidates.
Of all the identified knockouts, the removal of the gene that usually codes for the Tmx2 protein was observed to result in cell survival in almost all cases.
Study researcher and graduate student Michael Haney said: “We could imagine that Tmx2 might make good drug target candidate.
“If you have a small molecule that could somehow impede the function of Tmx2, there might be a therapeutic window there.”
Co-researcher Nicholas Kramer added: “We’re still in early phases, but I think figuring out exactly what Tmx2 normally does in a cell is a good place to start, that would hint at what functions are disturbed when these toxic species kill the cell, and it could point to what pathways we should look into.”
The researchers intend to use CRISPR screening to explore additional causes of ALS and other neurological diseases that also involve toxic proteins such as Huntington’s, Parkinson’s and Alzheimer’s.