New compound shows early promise for treatment of Lou Gehrig’s disease in preclinical models

(Press-News.org) In science, a simple but thorough observation can kick-start the most surprising findings. Researchers at the Hollings Cancer Center at the Medical University of South Carolina noticed that mice lacking a protein of interest in cancer research were showing visible signs of abnormal motor functions as they aged, including loss of coordination and strength. The team showed that that lack of this protein resulted in the accumulation of damaged mitochondria that affected motor function. Treating these mice with a drug that triggered the destruction of damaged mitochondria restored their motor function. This research was reported in Aging Cell.

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

“We did not expect to detect any neurological damage in our mouse model that lacks our protein of interest, as they had no symptoms when they were younger. However, when they aged, we were able to see the signs of neurological problems, like ALS,” said Besim Ogretmen, Ph.D., SmartState Endowed Chair in Lipidomics and Drug Discovery at MUSC, who leads the team of researchers working on this project, which includes Natalia Oleinik, Ph.D., first author of the article, and Onder Albayram, Ph.D., who performed the behavioral studies establishing neurological deficits in the mice.

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

The mice in Ogretmen’s study lack a protein called P17/PERMIT, which his team has studied for years in the context of cancer. The protein moves a certain enzyme to the mitochondria, which are the powerhouses of the cell and needed for proper cell function. However, when mitochondria are damaged or malfunction, cells must get rid of them to remain healthy. This process by which they do so is called mitophagy.

Mitophagy is triggered by the actions of P17/PERMIT. The role of the enzyme it transports to the mitochondria is to make molecules called ceramides. The production of these ceramides in the mitochondria is what’s needed to start the destruction of mitochondria that aren’t working properly.

When P17/PERMIT doesn’t exist, as in the case of Ogretmen’s mice, then this whole process is disrupted. Damaged mitochondria will not begin to self-destruct, and they will accumulate.

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

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

“We have a drug that can get past this lack of P17 and restore this mitophagy process,” he said.

For cancer, the drug is given in high doses so that it will accumulate in mitochondria and cut off the power supply to tumor cells. For neurodegenerative disease, the drug is given in lower doses and is intended to keep cells healthy by preventing the accumulation of damaged mitochondria.

In the study, older mice treated with this drug regained some of their coordination and strength.

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

While this drug is promising in mice, many challenges must be overcome before it will be useful in humans. One of the challenges that Ogretmen’s team had to work around was the fact that the drug was not able to pass through the barrier that protects the brain. They had to use special technology to allow the medication to get to the mouse brain with daily low doses. In upcoming research, the Ogretmen team will explore new ways for this drug to pass through the barrier more efficiently. They will also explore treating other diseases like Alzheimer’s disease.

“I am hopeful that we can overcome these challenges so that the drug can be a potential therapeutic agent to treat people with these diseases,” said Ogretmen.

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

# # #

About MUSC

Founded in 1824 in Charleston, MUSC is the state’s only comprehensive academic health system, with a unique mission to preserve and optimize human life in South Carolina through education, research and patient care. Each year, MUSC educates more than 3,200 students in six colleges – Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy – and trains more than 900 residents and fellows in its health system. MUSC brought in more than $298 million in research funds in fiscal year 2022, leading the state overall in research funding. MUSC also leads the state in federal and National Institutes of Health funding, with more than $220 million. For information on academic programs, visit musc.edu.

As the health care system of the Medical University of South Carolina, MUSC Health is dedicated to delivering the highest-quality and safest patient care while educating and training generations of outstanding health care providers and leaders to serve the people of South Carolina and beyond. Patient care is provided at 16 hospitals (includes owned and equity stake), with approximately 2,700 beds and four additional hospital locations in development; more than 350 telehealth sites and connectivity to patients’ homes; and nearly 750 care locations situated in all regions of South Carolina. In 2022, for the eighth consecutive year, U.S. News & World Report named MUSC Health University Medical Center in Charleston the No. 1 hospital in South Carolina. To learn more about clinical patient services, visit muschealth.org.

MUSC has a total enterprise annual operating budget of $5.1 billion. The nearly 26,000 MUSC family members include world-class faculty, physicians, specialty providers, scientists, students, affiliates and care team members who deliver groundbreaking education, research, and patient care.

END