Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease with a poor prognosis, but two new studies may point to a more optimistic future. Testing in human cells and live mice, scientists have identified genes and proteins that appear to be promising therapeutic targets.
Professor Stephen Hawking was an outlier. Most people diagnosed with ALS are expected to live no more than 2-5 years. The disease gradually destroys motor neurons, causing patients to lose muscle strength and mobility, eventually losing the ability to speak, eat, and even breathe.
Unfortunately, there are not many effective treatment options available. Therefore, a team led by the University of Southern California (USC) set out to explore new drug targets to treat ALS. Scientists first created induced pluripotent stem cells from ALS patients, programmed them into motor neurons, and then spun thousands on them to find the ones that might slow the progression of the disease. Screened drugs and molecules.
The team found that many effective drugs appear to increase androgens, a group of sex hormones that includes testosterone. We explored ways to circumvent drugs and induce the same effects by tweaking specific genes.
Using a database called Connectivity Maps, which links drugs to genes and related diseases, the team identified a gene called SYF2 that might be responsible. And sure enough, silencing this gene in mice with ALS attenuated neurodegeneration, motor dysfunction, and other symptoms.
“What is really interesting is that SYF2 inhibition ameliorated symptoms and pathologies associated with a protein called TDP-43, which can be toxic and is involved in nearly 97% of ALS cases. ,” said Yichen Li, co-first author of the study. .
A second study, conducted by some of the same scientists, used similar means to identify another culprit, a protein called PIKFYVE. In testing motor neurons grown from his ALS patients in fruit flies, roundworms, mice and humans, the team used drugs, genetic engineering and RNA technology to block proteins.
Again, treatment reduced neurodegeneration, improved motor function, and extended lifespan in subjects. Upon closer examination, the researchers identified the mechanism behind the improvement: reducing PIKFYVE helps neurons transport waste to the outside of the cell and prevents the accumulation of toxic proteins.
“We were able to pinpoint how PIKFYVE inhibition attenuates neurodegeneration, which is important to inform the development of new targeted therapies,” said co-first author of the study. One Shu-Ting Hung said:
There is still much work to be done before any of these strategies reach human trials, but it should help give hope that they have therapeutic potential.
First study published in journal cell stem celland the second cell.
Source: USC
