New drug shows exciting promise for the treatment of ALS

In science, a simple but thorough observation can initiate the most surprising results. Researchers at the Medical University of South Carolina’s Hollings Cancer Center observed that mice lacking a protein of interest in cancer research showed visible signs of abnormal motor functions as they aged, including loss of coordination and strength. The team showed that a lack of this protein results in an accumulation of damaged mitochondria that affects motor function. Treating these mice with a drug that destroys damaged mitochondria restored their motor function. This study is reported Aging cells.

Symptoms in these mice were similar to those seen in amyotrophic lateral sclerosis (ALS) patients. Commonly known as Lou Gehrig’s disease, ALS is a devastating neurodegenerative disease in which brain and muscle function declines over time. Few treatment options are available for ALS, and most patients die within two to five years of diagnosis. Results seen after treating study mice with the new drug show exciting promise for treating ALS.

“We didn’t expect to detect any neurological damage in our mouse model that lacked our protein of interest, because they had no symptoms when they were young. However, when they got older, we were able to see signs of ALS-like neurological problems. ” said Bessim Ogretman, Ph.D., the SmartState Endowed Chair in Lipidomics and Drug Discovery at MUSC, who led the team of researchers working on the project, including the article’s first author Natalia Olynyk, Ph.D., and Onder Albayram, Ph.D. who conducted behavioral studies establishing neurological deficits in rats.

“Being observant and careful in the lab has helped us uncover an interesting and unexpected process that could lead to innovative treatment options to overcome diseases like ALS in the clinic,” he said.

Ogretman’s study showed mice lacking a protein called P17/PERMIT, which his team has studied for years in the context of cancer. The protein carries a specific enzyme into the mitochondria, the powerhouse of the cell and essential for proper cell function. However, when mitochondria are damaged or dysfunctional, cells must get rid of them to stay healthy. The process by which they do this is called mitophagy.

Mitophagy is triggered by the action of P17/PERMIT. The role of the enzyme it transports to the mitochondria is to make a molecule called ceramide. The production of these ceramides in the mitochondria is to initiate the destruction of mitochondria that are not functioning properly.

When P17/PERMIT is absent, as in Ogretman’s mice, this entire process is disrupted. Damaged mitochondria will not initiate self-destruction and they will accumulate.

Damaged mitochondria also accumulate in neurodegenerative diseases, such as ALS, Parkinson’s, and Alzheimer’s disease.

Once Ogretmen’s team understood the mechanism behind this accumulation, they realized that they had already developed a drug in their cancer research that could target it.

“We have a drug that can overcome the p17 deficiency and restore this mitophagy process,” he said.

For cancer, the drug is given in high doses so that it accumulates in the mitochondria and cuts off the tumor cell’s power supply. For neurodegenerative diseases, the drug is given in low doses and is intended to keep cells healthy by preventing the accumulation of damaged mitochondria.

In studies, old mice treated with this drug regained some of their coordination and strength.

“They became almost like healthy mice of the same age.”

Bessim Ogretman, PhD, SmartState Endowed Chair in Lipidomics and Drug Discovery at MUSC

Although this drug is promising in mice, many challenges must be overcome before it can be effective in humans. One of the challenges Ogretman’s team had to work around was that the drug was unable to cross the barrier that protects the brain. They had to use special technology to deliver the drug to the mice’s brains in small doses every day. In upcoming studies, the Ogretmen team will explore new ways for this drug to cross barriers more efficiently. They will also explore treatments for other diseases such as Alzheimer’s disease.

“I’m optimistic that we can overcome these challenges so that the drug can become a potential therapeutic agent to treat people with these diseases,” Ogretman said.

He and another Hollings researcher, Shikhar Mehrotra, Ph.D., co-founded Lipo-ImmunoTech LLC, a biotech startup to design new drugs to treat patients or improve drug delivery.