Each year in the U.S., 5,000 patients receive a diagnosis of ALS, an incurable neurodegenerative disease that will likely kill them within two to five years. In the quest to find a cure for these patients, a team of researchers has identified two promising avenues for developing new treatments for diverse forms of this devastating disease, which is also known as amyotrophic lateral sclerosis or Lou Gehrig’s disease. Their findings are published in a pair of studies: the first appearing in the journal Cell Stem Cell , and the second in the journal Cell . 

“A minority of patients have a variety of genetic causes of ALS that can be inherited within families, and a majority have what is known as “sporadic” disease because its causes are unknown,” said a co-first author on both studies. “This makes it a difficult challenge to find one treatment that will work for all patients with ALS.”

To meet this challenge, the researchers collected skin or blood samples from patients with both familial and sporadic ALS. The scientists reprogrammed the skin and blood cells into motor neurons, which are the nerve cells responsible for movement that degenerate in the disease. These patient-derived motor neurons provided an opportunity to screen thousands of FDA-approved drugs and drug-like molecules to find ones that might be effective against multiple forms of ALS.

In the Cell Stem Cell study, co-first authors found that several of the most effective drugs and drug-like molecules increased the activity of androgens, the well-known group of sex hormones that include testosterone. However, because androgen-boosting drugs could have undesirable or unsafe side effects for patients with ALS, the scientists aimed to identify a genetic change that might yield similar results. 

To accomplish this, they leveraged a public bioinformatics database known as Connectivity Map. By analyzing this vast database of information about how drugs affect the genetic landscape underpinning diseases, the scientists accurately predicted that suppressing the SYF2 gene would increase the survival of motor neurons derived from patients with diverse forms of ALS. In addition, suppressing this gene reduced neurodegeneration, motor dysfunction, and other symptoms in mice with ALS. 

“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 percent of cases of ALS,” said a co-first author. 

In the second study published in Cell, co-first authors detail how inhibiting a protein, the PIKFYVE kinase, could represent another effective strategy for treating many different forms of ALS.

In an extensive series of experiments, the researchers inhibited PIKFYVE using the drug apilimod, as well as through genetic and RNA-based approaches, in fruit flies, roundworms, mice, and motor neurons derived from patients with different forms of ALS. 

They found that inhibiting PIKFYVE reduced neurodegeneration, improved motor function, and lengthened life by stimulating motor neurons to clear toxic proteins through a process of exocytosis, in which membrane-bound sacs envelop and actively transport waste to the exterior of the cell.

“We were able to pinpoint precisely how PIKFYVE inhibition mitigates neurodegeneration, which is important for informing the development of new targeted treatments,” said a co-first author.

https://www.cell.com/cell-stem-cell/pdf/S1934-5909(23)00005-X

https://www.cell.com/cell/fulltext/S0092-8674(23)00005-3