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Preclinical Test Advances Synthetic Bio ALS Treatment

Motorized wheelchair

(Kevin Phillips, Pixabay)

15 Dec. 2021. A candidate treatment for amyotrophic lateral sclerosis or ALS made with synthetic genetic material is shown to improve motor function and survival in lab mice. A team from the biotechnology company AcuraStem in Monrovia, California reported the findings last week in a poster at a virtual meeting of the Motor Neuron Disease Association.

ALS, also known as Lou Gehrig’s disease, is a progressive neurodegenerative disorder where neurons or nerve cells controlling muscles in the body begin to waste away, and can no longer send or receive signals from the brain or spinal cord. As the nerve cells stop functioning, the muscles in the limbs, and later speech and breathing muscles, begin weakening and eventually stop functioning. Most people with the disease die of respiratory failure. There are currently no cures for ALS, and few effective treatments for slowing progression of the disease.

AcuraStem is a five year-old enterprise that discovers new therapies from analysis of human motor neurons from patients with ALS and other neurodegenerative disorders. The company says it analyzes genetic underpinnings of diseased cells, with models aided by stem cells and machine learning to identify productive targets, then design and develop new therapies. AcuraStem is spun-off from the lab of neuroscientist Justin Ichida at University of Southern California, a co-founder of the company, who studies interactions between stem cells and neurons to discover therapies for neurological disorders.

Suppresses expression of dangerous protein

The company’s lead product, code-named AS-202, is designed as an antisense oligonucleotide, a short DNA or RNA sequence for altering RNA, thereby reducing, modifying, or restoring expression of proteins. In this case, AS-202 targets a protein known as PIKFYVE implicated in a range of infectious and chronic diseases. In ALS, PIKFYVE is associated with misallocation of another protein known as transactive response DNA binding protein 43, or TDP-43, which under stress, or as a result of a mutation, accumulates as excess toxic fragments. AcuraStem designs AS-202 to suppress expression of PIKFYVE, thus relieve stress on TDP-43 and help improve motor neuron functioning in patients with both sporadic and familial or inherited ALS.

A team led by AcuraStem’s head of research Wen-Hsuan Chang tested AS-202 in lab mice induced with aggressive TDP-43 accumulations. The researchers say mice treated with AS-202 show reduced levels of PIKFYVE proteins, which helps slow degeneration of nerve cells. As a result, mice receiving AS-202 show improved motor functioning and longer survival times. The company also reports AS-202 was well tolerated in the test mice, even in high doses, showing no off-target effects.

“These data make AS-202 a very promising drug candidate for the 97 percent of ALS patients that present with TDP-43 pathology,” says Peter Sazani, who heads translational medicine at AcuraStem, in a company statement. “The current preclinical data show that AS-202 could translate into an exciting new clinical approach to treating ALS.”

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