In brief

The IMCB research team are looking to test nicotinamide supplements in clinical trials to reduce ALS symptoms.

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Treating rare disease with familiar vitamins

19 Jan 2022

Metabolic changes in the neurons of patients with amyotrophic lateral sclerosis may be reversed with vitamin B3 supplements.

The health food aisles of supermarkets are typically packed with rows of vitamins and minerals, such as calcium for strong bones, zinc to stabilize blood sugar and vitamin A for eye health. But instead of just supporting optimal health, what if these off-the-shelf supplements could also help treat rare, incurable diseases?

This may soon be a reality for patients with amyotrophic lateral sclerosis (ALS), a debilitating disease that affects neural tissues and leads to the progressive loss of muscle control. Each year, around 400 Singaporeans are diagnosed with ALS, only to face limited and often ineffective treatment options. Of the two approved ALS drugs, Riluzole marginally extends lifespans, while Edaravone is only effective in a subset of patients.

At A*STAR’s Institute of Molecular and Cell Biology (IMCB), researchers led by Shi-Yan Ng are investigating novel druggable pathways involved in ALS along with collaborators from the University of California San Francisco. To identify new molecular targets for next-generation ALS drugs, Ng and colleagues used lab-grown ALS motor neurons and soon made a serendipitous find.

“A very observant laboratory researcher discovered that the ALS motor neuron cultures required more frequent media changes as the media color turned yellow more quickly,” explained Ng.

For the team, this observation suggested abnormalities in the ALS motor neurons’ metabolic pathways—with hyper-glycolysis churning out elevated levels of lactic acid to turn the pH indicator in the cell culture media yellow.

Taking a closer look at the imbalances in mitochondrial respiration in the ALS motor neurons, the team pinpointed a mitochondrial protein called SIRT3 as the culprit. Not only were activities of the SIRT3 protein much lower in ALS neurons than healthy ones, suppressing the SIRT3 gene in normal motor neurons made them almost indistinguishable from their diseased counterparts.

To explore potential avenues to reverse mitochondrial dysregulation, the researchers tested the effects of a Vitamin B3 derivative called nicotinamide on the ALS neurons. Upon nicotinamide treatment, the team observed striking changes in the ALS cells but not in healthy motor neurons.

“We demonstrated that nicotinamide supplementation effectively reversed mitochondrial defects and reduced disease phenotypes in the ALS motor neurons,” elaborated Ng.

Their findings highlight the key role of SIRT3 in ALS progression, and also show how common supplements like nicotinamide may help restore metabolic balance in diseased motor neurons as a novel therapeutic strategy.

To this end, Ng and the team are currently in talks with the National Neuroscience Institute to conduct clinical trials testing the effectiveness of nicotinamide supplements in reducing ALS symptoms. Though the researchers have already filed a patent related to the project, the search for effective ALS treatments continues.

“We will continue to screen for therapeutics that can improve mitochondrial function in the ALS neurons,” concluded Ng.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).

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Hor, J.H., Santosa, M.M., Lim, V.J.W., Ho, B.X., Taylor. A., et al. ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation, Cell Death Differ 28, 1379-1397 (2021) | article

About the Researcher

Shi Yan Ng completed her Bachelor in Science with First Class Honours at the National University of Singapore (NUS) and her Ph.D with Lawrence Stanton at the Genome Institute of Singapore, under the NUS Graduate School (NGSS) scholarship. With a keen interest in stem cells and modeling neurological disease, Ng joined Professor Lee Rubin’s laboratory at Harvard University to study Spinal Muscular Atrophy, an inherited motor neuron disease affecting children. Thereafter, Ng began her independent research career at IMCB in 2015, where she continued to study mechanisms of neurological diseases using patient-derived induced pluripotent stem cells. Shi Yan has won several fellowships and awards for her work, including the National Research Foundation (NRF) Fellowship (Class of 2018), the A*STAR International Fellowship (2012), and the Merck Millipore Young Scientist Award (2011). She is currently a Principal Investigator at IMCB, and an Assistant Professor at the Department of Physiology, NUS Medicine.

This article was made for A*STAR Research by Wildtype Media Group