Researchers Use CRISPR to Identify New Drug Targets for Amyotrophic Lateral Sclerosis

Researchers Use CRISPR to Identify New Drug Targets for Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) – also known as Lou Gehrig’s disease – is a neurodegenerative disease that results in progressive loss of motor neurons in the brain and spinal cord. ALS causes muscle weakness and ultimately paralysis. Patients diagnosed with the disease usually die within 2-5 years. There is no treatment that can cure the disease.

Neuronal death is the result of the formation of protein aggregates in the brain. While it is known that the protein aggregates are toxic to neurons and ultimately lead to neuronal death, it is unclear exactly how and why neuron death occurs.

Researchers from Stanford University School of Medicine conducted a novel study to investigate how neuronal cell death occurs using CRISPR-Cas9 technology. While CRISPR-Cas9 could potentially be used to alter genes involved in the development of the disease, the Stanford researchers used CRISPR to identify potential drug targets that could slow the spread of the disease.

It was previously known that mutations in the C9orf72 involve large numbers of repeating segments of DNA. While there are repeated segments in healthy individuals, they are limited to between 10 and 20. In individuals with ALS there are hundreds or thousands of repeats. These repeats result in the formation of dipeptide-repeat proteins (DPRs) that clump together and ultimately lead to neuronal death.

The researchers used CRISPR technology to identify genes that helped protect neurons against the toxic effects of the protein aggregates and gained insights into how neuronal cell death occurred, but also identified genes that helped to protect neurons from the toxic effects of the protein aggregates. Some of the identified genes have potential to be targeted by drugs that could help slow the progression of the disease.

The team performed genome-wide knockout screens in human cells to identify genes that could help to prevent cell death from the DPR proteins. The technique allowed the researchers to rapidly identify potential helpful genes, rather than testing each individually. The team identified around 200 genes in the initial screens that either protected cells from the toxic effects of the proteins or increased their toxicity. Further screens were performed to identify potential drug targets. One of the most promising targets was a gene called Ymx2, which was found to prevent neuronal cell death in mouse neurons.

“We could imagine that Tmx2 might make good drug target candidate,” -author of the study, Michael Han. “If you have a small molecule that could somehow impede the function of Tmx2, there might be a therapeutic window there.”

The research is detailed in the paper – CRISPR–Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity – recently published in Nature Genetics.

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