Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease with poor outcomes, but a pair of new studies may point towards a more optimistic future. In tests in human cells and live mice, the scientists identified a gene and a protein that look like promising targets for treatment.
Professor Stephen Hawking was an outlier – most people diagnosed with ALS are expected to only live another two to five years. The disease progressively destroys the motor neurons, reducing a patient’s muscle strength and mobility, until they eventually lose the ability to speak, eat or even breathe.
Unfortunately, there aren’t many effective treatment options available. So a team led by the University of Southern California (USC) set out to investigate new drug targets for treating ALS. The scientists started by creating induced pluripotent stem cells from ALS patients, programming them into motor neurons, and then screened thousands of drugs and molecules against them to find ones that may slow progression of the disease.
The team noticed that many effective drugs seemed to boost androgen, a group of sex hormones that includes testosterone. But since those drugs come with unwanted side effects, the researchers explored ways to side-step the drug and induce the same effect by tweaking specific genes.
Using a database called the Connectivity Map, which links drugs to genes and associated diseases, the team identified a gene called SYF2 that seemed to be responsible. And sure enough, when they suppressed this gene in mice with ALS, their neurodegeneration, motor dysfunction and other symptoms were reduced.
“What’s really exciting is that SYF2 suppression improved symptoms and pathology related to a protein called TDP-43, which can become toxic and is implicated in close to 97% of cases of ALS,” said Yichen Li, co-first author of the study.
In a second study, conducted by some of the same scientists, similar means were used to identify another culprit: a protein called PIKFYVE. In tests in fruit flies, roundworms, mice and motor neurons grown from human ALS patients, the team blocked the protein using drugs, genetic engineering and RNA techniques.
Once again, the treatment reduced neurodegeneration, improved motor function and increased the lifespan of the test subjects. On closer inspection, the researchers identified the mechanism behind the improvements – reducing PIKFYVE helped the neurons transport waste to the outside of the cell, which prevents toxic proteins from building up.
“We were able to pinpoint precisely how PIKFYVE inhibition mitigates neurodegeneration, which is important for informing the development of new targeted treatments,” said Shu-Ting Hung, co-first author of the study.
While there’s still plenty of work left to do before either of these strategies could ever make it to human trials, it should help provide hope that there are possible avenues of treatment out there.
The first study was published in the journal Cell Stem Cell, and the second in Cell.
Source: USC