Broad ALS targets show signs of success in treating genetic and sporadic forms 

There are two forms of the devastating degenerative nerve disease amyotrophic lateral sclerosis, or ALS. One has an established genetic basis, but the other's origin is still unknown despite it being far more common. While much progress has been made on drugs to treat genetic ALS, researchers have struggled to find therapies that work well in the second type, known as sporadic ALS.

But new developments may be on the horizon. A pair of studies published in early February from researchers at the biotech startup AcuraStem and the University of Southern California validated two potential drug targets in animal models of both genetic and sporadic ALS, paving the way for broad treatments.

“I think there are some very promising drug candidates that really seem to change the disease course in the known genetic forms of the disease,” Justin Ichida, Ph.D., senior author of the studies and co-founder of AcuraStem, told Fierce Biotech Research in an interview. “But we were hoping to find ways to have that kind of transformative potential for the larger patient population for whom we don’t know their genetic causes.”

The first study, published Feb. 2 in Cell Stem Cell, showed that suppressing the gene SYF2 boosted the survival of motor neurons grown from the stem cells from patients with either genetic or sporadic ALS. Their analyses showed that SYF2 was manipulating the protein TDP-43, which is thought to drive pathology in both forms of the condition due to being misplaced in the cytoplasm of motor cells rather than the nucleus. Experiments in mouse models of genetic and sporadic ALS also showed that SYF2 suppression improved motor function and reduced neurodegeneration.

The second study, published Feb. 7 in Cell, was more expansive: The researchers used a drug called apilimod to inhibit the enzyme PIKFYVE in human motor neurons, roundworms, fruit flies and mice with genetic or sporadic ALS. In this case, the drug prompted motor neurons to clear out toxic proteins, improving motor function and extending survival in all the models.

While the SYF2 findings are new, PIKFYVE has been a target of interest for ALS for a while by AcuraStem as well as Verge Genomics. “The research published in Cell further validates PIKFYVE as a promising therapeutic target in ALS and sheds light on a novel mechanism for clearing pathological protein aggregates,” Robert Scannevin, Ph.D., chief scientific officer at Verge, said in an emailed response to a request for comment. “Verge identified PIKFYVE as a target in our CONVERGE platform, and it is encouraging to see robust, independent validation across a number of sporadic and familial in vitro and in vivo ALS models.”

Last November, Verge launched a phase 1 clinical trial of a small-molecule PIKFYVE inhibitor. For its part, AcuraStem's PIKFYVE inhibitor is in IND-enabling studies on an antisense oligonucleotide (ASO).

AcuraStem was initially focused on small molecules like apilimod—which AI Therapeutics is testing in a phase 2 ALS trial—but has shifted its focus to ASOs, short nucleotide sequences that disrupt DNA or RNA to alter the levels of toxic proteins. ASOs for other targets in ALS are already in development by Biogen, Ionis and others, though most are for treating genetic forms of the disease.

“What we saw in our studies was that the ASO is more effective in vivo than the small molecule,” AcuraStem CEO and co-founder Sam Alworth said. The company licensed the PIKFYVE inhibitor from USC and is choosing to advance that drug first while it works on developing a small molecule that’s equally effective in animal models, he added. AcuraStem's SYF2 drug is an ASO as well. 

Ichida and AcuraStem also believe PIKFYVE inhibitors could be used to treat other neurodegenerative diseases, as there is overlap in the misfolded proteins found in those conditions and the ones seen in ALS. In conjunction with their PIKFYVE-targeting ASO for ALS, they’re also working on one for frontotemporal dementia.

“I think there’s potential for this to be useful beyond ALS,” Ichida said.

Editor's note: A previous version of this story misnamed Verge Genomics as Verge Therapeutics and incorrectly described its first clinical trialthe company in November dosed its first healthy volunteer, not its first patient, in the trial.