Regenerative Medicine Biotrust provides hope for patients with Best disease

Eleven-year-old Madison's sight had never been great — she first wore eyeglasses at age 4, starting with a +3D prescription. Then at age 6, local doctors noted bilateral macular scarring and referred her to Mayo Clinic.

Jose S. Pulido, M.D., an ophthalmologist at Mayo Clinic's campus in Rochester, Minnesota, evaluated Madison and diagnosed autosomal recessive bestrophinopathy, a rare recessive form of the already rare Best disease, an inherited form of macular degeneration.

Best disease usually does not impair vision until later in life, which made Madison's early onset difficult to detect. Her even rarer recessive form of Best disease makes it just as difficult to predict her prognosis. Although she is unlikely to become completely blind, legal blindness is a real possibility and there is currently no treatment to prevent it.

Innovative stem cell treatment

In August 2013, Alan D. Marmorstein, Ph.D., an expert on Best disease at Mayo Clinic's campus in Minnesota, proposed the development of an innovative stem cell treatment to help Madison. If successful, the treatment could help people with Best disease around the world.

Dr. Marmorstein has worked on Best disease since 1998, when the gene that causes the disease was discovered. He believes that bioengineered stem cells might halt the disease's progression, or even cure it. Mayo Clinic's Center for Regenerative Medicine has the capability to bioengineer induced pluripotent stem cells from adipose tissue and is pioneering methods to convert skin cells into stem cells for subsequent differentiation.

The center also houses the Regenerative Medicine Biotrust, which enables Dr. Marmorstein to test a number of possible treatments at once. Dr. Marmorstein has partnered with the biotrust to develop a regenerative medicine protocol focused on Best disease.

"We went from being experts in Best disease to being able to apply stem cells to Best because of the assistance of the biotrust experts," Dr. Marmorstein says. "I can't emphasize how critical they have been for this work. In one year, we've been able to accomplish what would have taken five years anywhere else."

RPE cell use for Madison

The biotrust converted Madison's skin samples into bioengineered stem cells and is now helping Dr. Marmorstein and colleagues convert those cells into functioning retinal pigment epithelial (RPE) cells — the cells affected by Best disease. The team will be able to test a number of possible treatments for Madison by working with the bioengineered cells before ever treating her.

The first potential treatment will be gene therapy. The team will also use the cells to test drugs that show promise but are not approved by the Food and Drug Administration for Best disease. Both of these approaches have drawbacks:

  • Gene therapy might lead to the unregulated expression of the protein involved in the disease
  • Medications always carry the risk of side effects

Dr. Marmorstein believes the most effective solution may be to remove Madison's damaged RPE cells and replace them with RPE cells bioengineered from her skin cells after the mutation causing the disease has been repaired. This approach could enable a permanent treatment with no potential side effects.

"Gene therapy doesn't remove the bad protein. Finding a drug would mean Madison would be on that drug for the rest of her life," Dr. Marmorstein says. "The best approach may well be to replace her RPE cells with new ones in which we have repaired the gene."

Information about Dr. Marmorstein's research in the use of stem cells as a cure for bestrophinopathies was published in Ophthalmology Update in 2014.

For more information

Disease-causing mutations exhibit disparate effects on the localization of bestrophin-1. Ophthalmology Update. 2014;4(3):2

Mayo Clinic. Stem cell models of Best disease and other retinal degenerative diseases. ClinicalTrials.gov.