Potential therapeutic target for multiple sclerosis

Apr 24 2007

Oregon Health & Science University neuroscientists are eyeing a protein as a potential therapeutic target for multiple sclerosis because de-activating it protects nerve fibers from damage.

OHSU researchers, working with colleagues at the Portland Veterans Affairs Medical Center and the University of Padova in Italy, have shown that genetically inactivating a protein called cyclophilin D can protect nerve fibers in a mouse model of multiple sclerosis. Cyclophin D is a key regulator of molecular processes in the nerve cell's powerhouse, the mitochondrion, and can participate in nerve fiber death. Inactivating cyclophilin D strengthens the mitochondrion, helping to protect nerve fibers from injury. The findings are published today in Proceedings of the National Academy of Sciences.

"We're extremely excited," said Michael Forte, Ph.D., senior scientist at the Vollum Institute at OHSU and the study's lead author. "While we can't genetically inactivate cyclophilin D in people, there are drugs out there that can block the protein. Our research predicts that drugs that block cyclophilin D should protect nerve fibers from damage in MS."

Such a drug would be the first therapy specifically for secondary-progressive MS, one of the more debilitating forms of MS involving an initial period of relapsing and remitting, followed by a steady worsening of symptoms. It affects half of the estimated 2 million people with MS.

The only available therapies for MS are anti-inflammatory drugs, which reduce the inflammation believed to spur certain T-cells in the body to attack myelin, the fatty sheath insulating nerve fibers in the brain and spinal cord. The fibers can't conduct impulses, leading to paralysis, memory loss, dizziness, fatigue, pain and imbalance. Over time, the nerve fibers themselves degenerate, leading to permanent functional deficits.

"All MS drugs available right now are anti-inflammatory," said study co-author Dennis Bourdette, M.D., professor and chairman of neurology in the OHSU School of Medicine, and director of the OHSU MS Center of Oregon. "What is desperately needed is a therapeutic that protects the nerve fibers from degeneration."

In recent years, scientists have increasingly viewed MS as a neurodegenerative disorder rather than simply an inflammatory one. Loss of nerve cells, injury to nerve fibers and atrophy within the central nervous system occur progressively from the start of the disease, eventually leading to permanent disability, especially in patients who've had MS for many years.

"What puts people in wheelchairs from MS is not an inflammatory attack on myelin of the central nervous system. It's the severing of the axons (nerve fibers), which is a permanent thing," Forte said.

Inflammation triggers a chain of molecular events that leads to progressive nerve fiber deterioration in MS, including the development of free radicals such as reactive oxygen and nitrogen that slow the cell's energy generation capability. It also throws off mitochondrial function by causing calcium to build up in the cell, reducing levels of ATP that serves as the cell's fuel source.

But scientists believe that cyclophilin D is responsible for causing the unregulated opening of a pore in the mitochondrion's membrane that allows the calcium overload. The OHSU team showed that mice lacking cyclophilin D still developed an MS-like disease, but unlike their counterparts possessing the protein, the mutant mice partially recovered. Scientists found their nerve fibers remained intact, and they resisted the free radicals and calcium overload.

"What we've done is make it so the mitochondria can tolerate higher loads of calcium before they die," Forte said. "The mutant mice are protected from axonal damage associated with this MS-like disease in mice."

The scientists are now testing drugs that could be used to shut down the cyclophilin D protein and the mitochondrion pore it activates. "If you basically inhibited that protein with a drug, you would see the same axonal preservation that you saw in the mutant mouse," Forte said.

One class of compounds Forte and Bourdette are particularly interested in is non-immunosuppressive derivative of cyclosporin A (CsA). Some nonimmunsuppressive derivatives of cyclosporin A are in human trials for other conditions. Because these drugs are already being tested in humans, they could be rapidly tested in MS. Bourdette believes that a cyclophilin D antagonist could potentially become available as a treatment for MS within five years.

"We don't have to invent the drugs to target this protein. They already exist," Bourdette said.

Such a therapy can't come soon enough for 36-year-old West Linn, Ore. resident Laura Wieden, who has suffered since 1995 from relapsing-remitting MS that's caused weakness in both legs and forced her to ride a Segway personal transportation device or a wheelchair. "For me, it's fabulous," she said. "If you can prevent MS, that's great, but what about the millions of people who have it, They need something that keeps the cells from dying. This just holds so much promise."

Wieden's father, Dan Wieden, co-founder of Portland-based Wieden + Kennedy advertising agency, set up a fund in his daughter's name , the Laura Fund for Innovation in Multiple Sclerosis Research , to support MS research that pushes traditional boundaries to discovery. The discovery by Forte, Bourdette and their team, which was funded in part by the foundation, fits the bill, he said.

"It goes to prove that sometimes the big breakthroughs do not come from the more traditional lines of inquiry," he said. "What I appreciate about our relationship with OHSU is that there seems to be a sense of urgency about these projects. And it's been beneficial for us to develop a more personal relationship with the researchers. That way it becomes not just an academic exercise, but a very passionate inquiry on their part."