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AcuraStem (acurastem.com), a patient-based company developing novel therapeutics for amyotrophic lateral sclerosis (ALS) and neurodegenerative diseases, announced the results of extensive preclinical studies on its lead program AS -202 for ALS patients. The data were presented on December 9 at the 32nd Motor Neuron Disease Association International Symposium on ALS /MND by Dr. Wen-Hsuan Chang, AcuraStem’s Director of Research.

AS -202 is a PIKFYVE suppressive antisense oligonucleotide optimized for both safety and efficacy as a potential treatment for motor neuron degeneration due to TDP-43 pathology in ALS patients.

A major feature of ALS disease pathology is the mislocalization of the DNA/RNA-binding protein TDP-43 from the nucleus of neurons, where it normally resides, to the cytoplasm, where it is associated with cytoplasmic aggregates in 97% of ALS cases.

The poster presentation AS -202, an effective and safe PIKFYVE suppressive antisense oligonucleotide therapy for familial and sporadic ALS, demonstrated that lowering PIKFYVE levels significantly improved motor function and survival in an aggressive TDP-43 mouse model of ALS. These improvements were driven by a rescue of motor neuron degeneration and TDP-43 pathology in treated mice. Importantly, the data demonstrate that AS -202 is a potent PIKFYVE suppressor without significant off-target effects in human cells and was well tolerated at high doses in rodent models.

“These data make AS-202 a very promising drug candidate for the 97% of ALS patients that present with TDP-43 pathology,” said Peter Sazani, Ph.D., Head of Translational Medicine at AcuraStem. “The current preclinical data show that AS-202 could translate into an exciting new clinical approach to treating ALS.”

The disease-modifying potential of PIKFYVE for ALS was discovered by AcuraStem co-founder Justin Ichida, Ph.D., in a groundbreaking study that appeared in Nature Medicine in 2018 (Shi Y et al Nature Med 2018). AcuraStem’s iNeuroRx® technology platform, which combines patient-derived disease models and human genetic data at scale, has validated Dr. Ichida’s discovery in many ALS patient-derived models, including both sporadic and multiple, genetically defined forms of ALS.

“Mislocalization of TDP-43 in motor neurons is a nearly universal finding in humans with ALS, and approaches to addressing this issue are extremely promising,” added Jeremy Shefner, M.D., Ph.D., of Barrow Neurological Institute. “Restoration of TDP-43 in the nucleus and reduction in cytoplasmic aggregates by PIKFYVE suppression is a strategy clearly worthy of future study.”

AcuraStem’s development of AS -202 is funded in part by the Alzheimer’s Drug Discovery Foundation, the Department of Defense Research Program (DOD) ALS under contract W81XWH2110355 and the National Institute Of Neurological Disorders And Stroke of the National Institutes of Health under Award Number R44NS124454. The contents are those of the author(s) and do not necessarily represent the official views of DOD or the U.S. government.