Research Feature

Mighty Mesenchymal

Researchers band together to harness the power of adult stem cells to fight disease

by Tamar Nordenberg

Mesenchymal under microscope

The rattling news came five years ago: It was multiple sclerosis (MS) that was steadily leeching the strength from gym owner and personal trainer Bill White. Pre-disease, the fitness enthusiast had weight-lifted his way to a brawny 233 pounds, but in his early 40s, the frustrating clumsiness, fatigue and weakness became gradually more disabling and harder to ignore.

"I tried to keep going," says White, who also owned a flooring company and fought with all his might to keep MS from hijacking his chock-full life. Still, he says, "It finally hit me—I couldn't keep up with it all anymore."

The autoimmune disease, White was warned, would lead to deterioration of muscle control, balance and vision, as his immune system attacked his central nervous system, damaging his nerve cells and their protective myelin sheath. Doctors prescribed standard MS medications glatiramer acetate (Copaxone) and then interferon beta-1a (Avonex)-drugs that slow the disease but, unfortunately, are powerless to reverse the nervous-system damage caused by the disease process. However, White says, the meds caused intolerable side effects: His appetite all but disappeared, and he felt he was wasting away.

After two years and 53 pounds lost, the former standout football player and wrestler considered "stopping all the shots, and going all-natural." Acknowledging that protein shakes and fruits and vegetables alone would be no match for his condition, though, White and his wife toyed with going abroad for much-hyped unconventional treatments they read about online, but the money wasn't there.

Then, White found hope close to his suburban Cleveland home. His neurologist Jeffrey Cohen, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and director of the Mellen Center's Experimental Therapeutics Program at Cleveland Clinic, was gearing up for a new multiple sclerosis study. He wasn't researching a new drug, but, rather, a way to empower the body's own mesenchymal stem cells (MSCs) to treat the disease.

The study, now in full-swing, joins lead investigator Cohen with other School of Medicine faculty members who practice at clinical affiliates University Hospitals (UH) Case Medical Center and Cleveland Clinic. They are testing the safety of MSCs in multiple sclerosis patients like White—taking the first step toward harnessing the body's inner abilities to fight a disease that affects more than 2.5 million people around the world.

Bill White
Bill White, diagnosed five years ago with MS, says he feels less tired and is able to walk better since receiving an MSC transplant as part of the clinical trial.
Sending a Signal

Mesenchymal stem cells are found in several tissues, including adult bone marrow, and can differentiate into bone, tendon and other connective tissues. Much mystery still shrouds the precise mechanics of MSCs, but researchers have identified three characteristics of these particular stem cells that make them especially useful tools.

First, when administered intravenously, they are able to spot areas of inflammation and damage and wend their way through the bloodstream to where they are needed. Second, they have the ability to regulate the immune system to decrease an overactive inflammatory response, while blocking formation of scar tissue. And, third, they can regenerate tissue-not by turning into tissue themselves as some stem cells are known to do, but by providing healing instructions to other repair mechanisms at the injury site.

"MSCs' response to their environment is remarkable," says Stanton Gerson, MD, the Asa & Patricia Shiverick and Jane Shiverick (Tripp) Professor of Hematological Oncology at the School of Medicine, director of the school's National Center for Regenerative Medicine and Case Comprehensive Cancer Center, and director of UH Case Medical Center's Seidman Cancer Center. "When they find themselves in an inflamed place, they shut down inflammation. If they find themselves in a wounded place, they help it heal. If they find themselves in a place overrun by bacteria, they fight off the infection." The cells' adaptability, Gerson says, could someday translate into an expansive clinical role for the cells. (See "A Range of Research")

Renowned researcher Arnold Caplan, PhD, a professor of biology at Case Western Reserve, suggests MSC could more aptly stand for "medicinal signaling cell." He calls them the body's "drugstore" because once they reach the place they're needed, they help the body heal itself as it should naturally do.

A New Spin on Stem Cells

MSCs have been hailed over the years as a method-in-the-making to grow replacement parts for damaged organs. While this line of study is slowly progressing, the Cohen-led clinical trial is looking at the cells in a very different way: They are taking an MS patients' mesenchymal stem cells from their own bone marrow, isolating the cells in a laboratory to boost their numbers, and returning them intravenously to the patients to see if they can halt the progression of multiple sclerosis or even reverse the disease by repairing harmed tissue. (See "Multi-institutional Effort")

White is among the 24 patients to be recruited for the study-all with relapsing or progressively worsening MS and with moderate to severe disability from the disease.

As a Phase I trial, the study is designed to focus on safety. But the tests will also shed light on functional improvement, emphasizes Robert Miller, PhD, professor of neurosciences, vice president for research at the university and the researcher whose basic science studies inspired the clinical trial. Preliminary findings are expected in 2012, with updates to follow.

For his part, White says he felt improvement within weeks of receiving the MSC transplant. He says he's less tired than before the study, and he can lift his left leg under its own power, where he used to use his arm to assist. "Within just two months," he says, "three people noticed I was walking better. And people are saying 'you look better.' "

From Clues to Clinics

It has taken decades of research to bring scientists to today's understanding of MSCs and their potential in medicine. Since the late 1980s, Case Western Reserve's Caplan has been front-and-center in the study of MSCs as building blocks for engineered tissues and organs. And Caplan-who has been referred to as the "American Father of MSCs" by stem cell pioneer Hillard Lazarus, MD-developed the technique for growing MSCs isolated from the bone marrow into large numbers of cells.

Caplan started working with Miller in 2003. Their basic-science studies showed how human MSCs can promote healing and protect against a destructive autoimmune response. Caplan recalls the results: "The mice were cured of their MS-like disease. Not only did the MSCs stop the immune attack that led to myelin damage, but the animals remyelinated."

What was more, the animals showed no signs of rejecting the human cells. MSCs seem to be "immunologically privileged," says Lazarus, professor of medicine at the school, director of the Novel Cell Therapy Program at UH Seidman Cancer Center, and the stem-cell expert who initiated the first U.S. clinical trials with MSCs in 1991. He adds this so-called immunity also has been shown in person-to-person transplantation. "MSCs can set up shop in a different host without being recognized and knocked out." This characteristic broadens the cells' potential usefulness to include allogeneic transplant, in which patients receive stem cells from a donor rather than their own cells.

Based on these heartening results from preclinical studies, Caplan and Miller encouraged multiple sclerosis expert Cohen to develop the current clinical trial protocol, which won a $2.75 million, four-year grant from the U.S. Department of Defense and a $1 million grant from the NIH.

This kind of multi-institutional collaboration, where investigators combine individual expertise to see research through from the basic biological underpinnings to preclinical testing to intricate clinical trials, Caplan says, is a hallmark of Cleveland-area research. It's this collegial atmosphere that sets the city apart from other medical research hubs, he says. And it's the kind of attitude that attracted him to the area more than 40 years ago and that has kept him moored throughout the decades.

"World-class experts can walk across campus and talk to each other," he says. "It's great, the way top experts in different subspecialties get together here and play ball."

Progress and Predictions

While the multiple sclerosis clinical trial is still in its early innings, Cohen says no side effects or complications have been seen from the safety data so far. Given positive results from this trial once it is complete and from follow-up trials, the therapy could be widely available to patients with MS within seven to 10 years, by the lead investigator's estimate.

White, for one, won't have to wait that long. He says the procedure—in concert with his dogged determination not to fall victim to the call of his wheelchair, even when walking gets hard—has already done for him what standard medications could not.

"I'm starting to get back what MS took from me for five years. I see some of my stamina coming back, and my hope is that I'll get 100 percent better," he says.

DISCLOSURE: Arnold Caplan, PhD, founded the company Osiris Therapeutics, Inc (OTI), which is commercializing mesenchymal stem cells. Osiris sends royalties to Case Western Reserve University for certain applications of mesenchymal stem cells, and these royalties are shared with Caplan, Stanton Gerson, MD, and other Case Western Reserve University inventors. Gerson is a director of research centers at both University Hospitals Case Medical Center and Case Western Reserve University, and he has an ownership interest in Osiris.