Novel delivery may enhance stem cell efficacy in fistulizing Crohn's

Complex perianal fistulas, which may affect up to 40 percent of people with Crohn's disease, can have a profound impact on quality of life. Yet the limitations of current treatments make multidisciplinary management of this condition extremely challenging. In many patients, the ideal goal — complete and sustained fistula closure — is never achieved, and recent improvements in medical and surgical therapies have not solved the problems of poor wound healing, recurrence and incontinence.

"Over the years, different approaches have been used to fill and cover the defective tissue and allow it to regrow in a healthy way, but most of these approaches have failed," notes Eric J. Dozois, M.D., associate program director for general surgery at Mayo Clinic in Rochester, Minn. For instance, initial reports demonstrated high success rates for bioprosthetic fistula plugs — a finding not borne out in subsequent studies.

Dr. Dozois explains, "It's hard to have a standardized cohort with the same biological environment, so there are many factors that may complicate the data, but once more centers used the plug and published the data, no one could match the original 70 to 80 percent success rate. Actually, there is about a 30 percent chance that a plug, in and of itself, will be successful in the first two years. So, though plugs are exciting and encouraging, they didn't quite get us there."

In the past decade, however, another approach — cell therapy, in which stromal cells are cultured and expanded to produce autologous adult stem cells — has emerged as a compelling option for wound healing in a variety of settings. In trials involving treatment of fistulizing Crohn's disease, the cells are injected around the fistula opening and directly into the fistula tract. Early studies in Europe and Asia have demonstrated sustained complete closure in a majority of treated patients.

"Stem cells give the body's own immune response a boost; it's a turbo-charged approach to healing," Dr. Dozois says. "We can't heal fistulas with surgery; all we can do is control infection and make sure things aren't getting out of hand. Stem cells offer a way to rebuild, reconstruct, regenerate."

But Dr. Dozois' enthusiasm for stem cells does not extend to the current method for delivering them. "Injecting stem cells is like throwing darts at a dartboard. It occurred to me we could try impregnating a fistula plug with the cells and so deliver them more directly."

Now, a Phase I clinical trial is underway at Mayo Clinic in Minnesota that proposes to do exactly that: determine the safety of adipose-derived mesenchymal stem cell transfer using a biomatrix in fistulizing Crohn's disease. It is the first study to do so.

Study sponsor, William A. Faubion, M.D., notes, "Previous studies were done in the setting of fibrin glue. We wanted to grow the cells on a matrix, which turned out to be synthetic. The cells wouldn't stick to the porcine intestine plug, but they loved the synthetic one."

Allan B. Dietz, Ph.D., co-directs Mayo Clinic's Human Cellular Therapy Laboratory, which has been developing stem cell technologies for various clinical indications for more than six years and will provide cells for the current study.

"We are a group of clinicians and translational scientists interested in bringing cells as drugs to patients," Dr. Dietz says. "We have spent six years preparing cells for clinical use, not studying them in mice. These studies are very hard to get funded, but we have a group of private donors who have enabled things like this to happen."

Trial design

Mayo investigators hope to enroll 20 patients with perianal fistulizing Crohn's disease in the study.  Each will undergo standard adjuvant therapy, including infection drainage and placement of a draining seton. After six weeks, the seton will be replaced with a fistula plug containing 20 million autologous mesenchymal stem cells, which have been cultured and expanded from a small fat biopsy collected from each patient.

Patients will be followed for fistula response and closure for 24 months. Short-term success is defined as complete closure at three months and long-term success as sustained closure at one year.

Dr. Dozois says, "If this is successful, patients will no longer have recurring infections or have to undergo multiple operations ultimately leading to a permanent diversion. That is the impact this could have. If damaged tissue can be reversed, remodeled or replaced, then we no longer have to crudely remove parts of people's bodies. This approach allows us to try to rebuild what was originally there."

He adds, "The important message for patients and referring physicians is that we are studying and developing new regenerative therapies and may have something definitive in a year or two. If patients can hang on and not undergo major surgeries, there may be a solution just around the corner."

Dr. Dietz concurs, saying, "This is the last big frontier in medicine. First there was surgery, then drugs. Now regenerative medicine comes to the fore as we begin to understand the ability of the body to heal itself."

For more information

Contact Gwen M. Boe, R.N., at 507-266-9917 or boe.gwen@mayo.edu.

A Phase 1 Study of Autologous Mesenchymal Stromal Cell Coated Fistula Plug in Patients With Fistulizing Crohn's Disease. Mayo Clinic Clinical Trials.

Stem Cell Fistula Plug in Perianal Crohn's Disease (MSC-AFP) Clinical Trials.gov.