Novel delivery may improve stem cell efficacy in fistulizing Crohn's disease

Complex perianal fistulae manifest as fissures in the gut wall, surrounded by granulation tissue with acute and chronic inflammation. They affect as many as 40 percent of people with Crohn's disease (CD), are associated with significant morbidity and have a profound effect on quality of life. 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," says Eric J. Dozois, M.D., a colon and rectal surgeon at Mayo Clinic's campus in Minnesota. For example, the initial demonstrated high success rates for bioprosthetic fistula plugs were 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."

More recently, stem cell therapy, in which adipose-derived stromal stem 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 CD, the cells are injected around the fistula opening and directly into the fistula tract. Early studies have demonstrated sustained complete closure in a majority of treated patients. Unlike surgical and pharmaceutical approaches, stem cells are a way to rebuild and regenerate damaged tissue.

Nevertheless, injecting stem cells, usually in the setting of fibrin glue, is an inexact art. Dr. Dozois suggests that using fibrin plugs impregnated with stem cells may be a more precise and effective mode of delivery. To test this theory, a phase I clinical trial at Mayo Clinic's campus in Minnesota is evaluating the safety of adipose-derived mesenchymal stem cell transfer using a biomatrix in fistulizing CD. It is the first study to do so, according to the Mayo Clinic gastroenterologist and study sponsor, William A. Faubion, M.D.

Stem cells for the study are provided by Mayo's Human Cellular Therapy Laboratory, which has been developing stem cell technologies for various clinical indications for close to a decade.

Trial design

Mayo investigators hope to enroll 20 patients with perianal fistulizing CD 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 explains: "If this is successful, patients will no longer have recurring infections or have to undergo multiple operations ultimately leading to a permanent diversion. This approach allows us to try to rebuild what was originally there. 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."

For more information

Faubion WA. Stem Cell Fistula Plug in Perianal Crohn's Disease (MSC-AFP). ClinicalTrials.gov.