Feature Story | 3-Nov-2023

USC Stem Cell research advances toward clinical development of treatments for ALS

The advance of research from Justin Ichida’s lab follows a license agreement between companies Takeda and AcuraStem.

Keck School of Medicine of USC

USC Stem Cell scientist Justin Ichida has learned to inhabit two worlds: the university where his lab makes discoveries, and the companies that can help commercialize these discoveries into new treatments for neurodegenerative diseases. The first of these potential treatments now has the potential to enter clinical development for patients with amyotrophic lateral sclerosis (ALS), following a recent license agreement between the pharmaceutical giant Takeda and AcuraStem, a startup co-founded by Ichida in 2016.

“The research that originated in my USC lab is approaching clinical development with a reputable biopharmaceutical company,” said Ichida, who is the John Douglas French Alzheimer’s Foundation Associate Professor of Stem Cell Biology and Regenerative Medicine at USC. “I could not have asked for a better, more supportive environment than USC for making this a reality.”

Not strictly academic

The project got off the ground in 2015, when Ichida’s lab at the Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research for USC teamed up with pharmaceutical company Sanofi and startup DRVision Technologies, and received a $1.5 million grant from the Department of Defense (DoD) to find new drugs to fight ALS. The DoD was interested in funding this research, because for reasons that are not yet understood, military veterans are more likely than civilians to be affected by this fatal disease, which typically leads to paralysis and respiratory failure within three to five years of diagnosis.

The Ichida Lab had already screened 800 drug-like compounds in the laboratory on motor nerve cells derived from patients with ALS. Originally, a robotic screening machine would expose the patient cells to the drug-like compounds and capture movies of the results, which lab members would pour over manually—counting and characterizing individual motor neurons for signs of life.

By working with DRVision, the lab gained access to image analysis software that automated the process of tracking motor neuron survival. This enabled them to scale-up the project and screen 2,000 approved drugs in the lab, and an additional 40,000 drug-like compounds at Sanofi.

The screen revealed that inhibiting a protein, called the PIKFYVE kinase, improved the survival of motor neurons from patients with the most common form of ALS. Ichida’s team published this discovery as part of a larger paper in Nature Medicine in 2018.

“We saw the potential of that and thought, ‘Let’s see if we can make a drug out of it,” said Ichida. “And we felt like the best way to do that was to form a separate company.”

Along with Sam Alworth from DRVision, Paul August from Sanofi, and Qing Liu from USC, Ichida co-founded AcuraStem, a startup dedicated to discovering new treatments for neurodegenerative diseases including ALS and frontotemporal dementia.

“We formed the company with great people, and it was very exciting,” said Liu, who was USC Stem Cell’s program director in charge of corporate partnerships and now works as the director of the Translational Development Center at City of Hope. “All the stars aligned, and it worked out well.”

An industrial strength research program

While the lab remained focused on publishing new discoveries in scientific journals, AcuraStem got to work on developing a potential therapy targeting PIKFYVE.

“We knew the task would not be easy, ” said Wen-Hsuan Chang, who became AcuraStem’s first employee after earning her PhD at USC, and currently serves as the company’s Head of Target Validation. “But we recruited team members with key areas of expertise and developed a potent and well-tolerated molecule. I feel extremely lucky that I got to work with the co-founders and my team members.”

The major source of AcuraStem’s funding was a type of grant only available to companies: Small Business Innovation Research (SBIR) grants from the National Institutes of Health (NIH). Additional support came from DoD, the Alzheimer’s Drug Discovery Foundation, the Harrington Discovery Institute, the Alzheimer’s Association, and the Rainwater Charitable Foundation.

“AcuraStem has raised a little over $20 million in grants,” said Ichida. “So that’s $20 million dollars towards the development of a drug-like compound that would have been more difficult to raise in the academic setting.”

At the same time, two other companies, Verge Genomics and AI Therapeutics, began developing small molecule-based drugs to target PIKFYVE, based on the Ichida lab’s findings. These drugs have also advanced to clinical trials for patients with ALS.

AcuraStem began by pursuing their own small molecule-based drug. However, through conversations with a team of drug development experts from the Harrington Discovery Institute, which had awarded a grant to the Ichida Lab, AcuraStem landed on a plan to develop an entirely different type of therapy known as an antisense oligonucleotide (ASO). Much larger than small molecules, ASOs are too big to cross the blood-brain barrier, and so are injected directly into the spinal fluid, where they can more specifically target neural tissue.

AcuraStem developed an ASO to suppress PIKFYVE, which has shown promising results and has outperformed small molecule PIKFYVE inhibitors in pre-clinical studies.

In early 2023, the Ichida Lab published a complementary paper in Cell, suggesting that PIKFYVE could be an effective target for treating many different forms of ALS.

The paper’s co-first author, Shu-Ting (Michelle) Hung, earned her PhD in the Ichida Lab and now works as a scientist at AcuraStem. “It’s really exciting to see things we have been working on in the lab for so many years take a big step forward, so we’re all really happy about that,” she said. “It’s huge.”

“It’s a very successful outcome in terms of our mission, which is to make better, more      effective treatments, and get them to patients as quickly as possible,” said AcuraStem’s CEO Sam Alworth.

AcuraStem will continue to conduct pre-clinical studies and characterize potential backup ASOs, while Takeda will take over clinical development, regulatory affairs, and global commercialization of the PIKFYVE program.

“I’m pretty excited, because I know that Takeda has outstanding neuroscience and clinical groups,” said Ichida. “This does seem like a major milestone, and we’re much closer now to really seeing how this is going to work in patients.”

Disclosure: Justin Ichida is a co-founder and equity holder, and sits on the Scientific Advisory Board of AcuraStem. USC is also an equity holder and has the potential to receive royalty payments from AcuraStem.

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