Big Step in Regenerative Medicine

New stem cell technique offers hope for those with corneal damage

surgeon's hands with implements

Video: Mass Eye and Ear

Harvard Medical School surgeons at Massachusetts Eye and Ear have replaced the ocular surface of four patients who each experienced chemical burns to one eye. The technique, cultivated autologous limbal epithelial cell transplantation (CALEC), uses stem cells taken from a patient’s healthy eye. These four cases are part of an ongoing clinical trial supported by the National Eye Institute and represent the first procedures of their kind to occur in the United States.

CALEC was developed by researchers at HMS, Mass Eye and Ear, Boston Children’s Hospital, and Dana-Farber Cancer Institute. Led by principal investigator Ula Jurkunas, HMS associate professor of ophthalmology and a cornea and refractive surgeon at Mass Eye and Ear, the team performed its first CALEC procedure as part of an ongoing clinical trial in April 2018.

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A small biopsy containing stem cells from the patient’s healthy eye that had been taken two weeks earlier was transported to the Connell and O’Reilly Families Cell Manipulation Core Facility at Dana-Farber, where, under the direction of Jerome Ritz, HMS professor of medicine at Dana-Farber, cornea (limbal) stem cells were expanded and grown on a membrane substrate. Once the cells had grown to cover the membrane and the graft was ready for transplant, Jurkunas performed extensive scar tissue removal and transplanted the CALEC onto the cornea.

Since then, three more patients have received the CALEC treatment. Two received a transplant after the first biopsy, and one did not grow enough cells on the first biopsy attempt, but underwent a second, successful biopsy and was able to receive a transplant. Cells from one additional patient enrolled in this phase of the study did not grow well enough to undergo the grafting procedure. Altogether, four of the five patients enrolled in this phase of the study received a CALEC transplant. The four patients who received the CALEC treatment no longer experienced pain from their initial chemical injuries shortly after the CALEC grafting procedures. The study will continue to follow these patients and monitor their progress.

Now that the technique’s feasibility has been established with no immediate safety concerns, the researchers have begun to recruit more patients with corneal damage into a second phase of the trial, which will continue through 2021. In addition to safety and feasibility, the outcomes of the CALEC technique will be investigated by evauating whether CALEC leads to improved vision either by itself or by enabling cornea transplantation.

Advance in regenerative medicine

“Using the patient’s own stem cells is a big step for regenerative medicine,” said Jurkunas, who is an affiliate faculty member of the Harvard Stem Cell Institute. “With this clinical trial, we hope to pave the way for better care for patients with corneal blindness, who have long needed better solutions for their condition.”

The process for isolating, growing and preparing limbal stem cells for transplantation was developed in collaboration with Myriam Armant, HMS instructor in pediatrics at Boston Children’s. “We worked closely with Dr. Jurkunas and Dr. Armant to implement the manufacturing process in our new Connell and O’Reilly Families Cell Manipulation Core Facility at Dana-Farber. The manufacturing process is carried out in a ‘clean room’ environment under strict quality-controlled conditions to maintain product sterility. The entire process takes approximately three weeks before the limbal stem cell graft is ready to be sent to the operating room at Mass Eye and Ear where Dr. Jurkunas performs the transplant,” said Ritz.

The cornea is the clear, outermost layer of the eye responsible for maintaining a smooth surface for normal vision. In the CALEC procedure, the surgeon takes stem cells from the limbus, the outer border of the cornea, where a high volume of stem cells reside in healthy eyes. Limbal stem cells help maintain the barrier between the cornea and the conjunctiva, the white areas on the sides of the eye.

In patients with chemical burns to the eye, the limbal area is often impaired to the point that new cells can no longer be created on their own. Limbal stem cell deficiency can also be caused by infections, complications from contact lenses and other conditions.

Beyond vision loss, patients with chemical eye burns often experience pain and discomfort in the affected eye. Current treatments include transplantation of an artificial cornea, which carries risk of infection and the development of glaucoma, or the conjunctival limbal autograft (CLAU) technique, which, compared to CALEC, involves taking a larger portion of cells from the healthy eye and transplanting them directly on the eye.

The goal of limbal stem cell transplantation such as CALEC and CLAU is to rebuild a healthy surface for the damaged eye using cells from the other eye, avoiding use of donor tissue; therefore, it can help only patients with limbal stem cell deficiency in one eye. Once a healthy surface has been restored, these patients are able to receive conventional corneal transplants—an outcome that was not possible before stem cell transplantation as limbal stem cells are needed to support the transplanted corneal tissue. Researchers hope that some patients may not need corneal transplants and may experience sight and ocular surface restoration with CALEC alone.

Lower risks for patients

The technique does not carry the risk of rejection like some other procedures because the cells are taken from the patient’s own body. Accordingly, patients who receive CALEC and CLAU do not need to take long-term steroids or immunosuppressive medications. Moreover, CALEC may have an advantage over CLAU as only one small biopsy from the donor eye is required, potentially decreasing the risk to the healthy eye.

This research originated in 2006, when Jurkunas received an NIH Production Assistance for Cellular Therapies (PACT) grant to examine ways to regenerate limbal stem cells. Since then, her team of clinician scientists from Mass Eye and Ear has made new discoveries related to corneal injury and received funding to develop stem cell regeneration techniques that would meet federal regulatory standards.

“Our team has put a tremendous amount of effort into developing the procedures for growing the grafts. So many conditions have to be just right so that the cells grow and the patient is safe. If we continue to be successful we will be able to give these patients with this condition a healthy surface of the eye—and possibly even restore vision to some,” said Jurkunas. “We are proud to have developed this novel treatment from the lab bench to the bedside in an academic medical setting, without industry support,” she adds.

“These early cases show great promise for a safe treatment option for people who have lost vision from chemical burns and corneal infections,” said Joan Miller, the David Glendenning Cogan Professor of Ophthalmology at HMS, chair of ophthalmology at Mass Eye and Ear, and chief of ophthalmology at Mass Eye and Ear, Massachusetts General Hospital, and Brigham and Women’s Hospital. “This novel and innovative technique to harvest stem cells from the healthy eye in an effort to heal the affected one was born out of Jurkunas’ lab more than a decade ago.”

The clinical trial represents the first human study of a stem cell therapy to be funded by the National Eye Institute (grants UG1EY026508, UG1EY027726 and UG1EY027725). Pretrial work was also funded by the National Heart, Lung, and Blood Institute’s initiative PACT.

Additional investigators include Jia Yin, Reza Dana, Lynette Johns, Hélène Negre and Allison Ayala.

Adapted from a Mass Eye and Ear and Dana-Farber joint news release.