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Molecule enhances effect of cholesterol-lowering drug

After completing his PhD dissertation at Oklahoma State University, M. Mahmood Hussain expected to continue working on plant viruses. Instead, a pair of post-docs at Boston University Medical Center and San Francisco General Hospital pointed him toward human lipoproteins, and in the decades since, he’s become a leader in the field.

“There was no grand plan,” says Hussain, distinguished professor of cell biology and pediatrics at SUNY Downstate Medical Center in Brooklyn. “I just wanted to get the next job, and it’s purely circumstance that I was exposed to this. At the time, I didn’t know if I was suited – I thought I might be able to do it, and might like it, and that was my route. But I never imagined I’d be here.”

Over the past fifteen years, Hussain has been teaching at SUNY Downstate, publishing close to one hundred papers, and receiving patents for his work in hyperlipidemia, elevated levels of fat in the bloodstream that dramatically increase the likelihood of cardiovascular disease, the number one cause of death in the United States. In 2013, writing in Nature Medicine, Hussain and his lab announced their most recent breakthrough: the discovery of an RNA molecule that could provide the basis for treating high cholesterol and hardening of the arteries, called atherosclerosis.

“If you lower lipids, then you lower atherosclerosis,” says Hussain. “That’s a well-studied risk factor, and that’s why statins have become such popular drugs. Statins work by removing lipids from blood plasma, whereas we’re studying ways to reduce the entrance of lipids into the blood plasma. It’s a complementary approach that would make statins more potent, and would be a significant advance in controlling fat absorption.”

Working with mice, Hussain demonstrated a connection between the genetic regulator microRNA-30c (miR-30c) and microsomal triglyceride transfer protein (MTP), which is necessary for the assembly of lipoproteins. By increasing miR-30c, Hussain reduced MTP activity, inhibiting lipoprotein production and decreasing the presence of lipids in the blood. Then, as confirmation, Hussain successfully increased lipoproteins by decreasing the levels of miR-30c.

“When you inhibit MTP, the risks are high,” says Hussain. “We were concerned that lowering lipids might cause liver toxicity, and that we might find fat accumulating in the liver. That’s why MTP inhibitors are only prescribed for select patients, because they’re not well tolerated. But we didn’t see that in the study, which was a shocker for us.

That’s what really got us excited.”

Now, with a $50,000 investment from the SUNY Technology Accelerator Fund (TAF), Hussain is ready to tackle the next question: Will a medication that mimics miR-30c produce the same results? Reaching that proof-of-concept milestone is a critical step in developing any new drug, and with more than one-third of American adults having high cholesterol, and more than one-third of American children being overweight or obese, the impact of turning Hussain’s theory into reality would be enormous.

“Can these mimics work?” he asks. “We don’t know. We’re going to begin these next experiments soon, and if the mimics work with mice, we’ll be ready to try them on monkeys. Being optimistic, we could know pretty quickly whether these mimics will work in mice and monkeys, and after that, the work would be out of our hands.”

If all goes well, a pharmaceutical company would take over from there, conducting the human trials that begin the process of bringing the new drug to market.

“I love research,” says Hussain, who has another half-dozen current projects that approach hyperlipidemia in different ways. “Every day I’m in the lab, there’s something new. I have been in this business a long time, coming up with new ideas, testing them out. Some of them work, probably one to two percent of the time, and I’m happy they do, as they lead us to new directions.”

Tags Tags: Downstate Medical Center , Technology Accelerator Fund

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