Can we restore sight?

November 7, 2018

Markus Frank and his colleagues are reprogramming skin cells with the goal of giving people back their sight.

  • Seed funding from HSCI led Markus Frank and his colleagues to discover that the cell surface molecule ABCB5 can be used to identify limbal stem cells, which regenerate the cornea.
  • The team is developing ABCB5-positive cell therapy as a treatment for vision loss due to limbal stem cell deficiency.

Markus Frank, M.D., co-leader of the HSCI Skin Program, is reprogramming stem cells from the skin with the goal of rebuilding the cornea – the clear, outer surface of the eye – in patients who have lost their sight.

Quote from Markus Frank, M.D.

Markus Frank, M.D., Associate Professor of Pediatrics and Dermatology, Harvard Medical School and co-lead of the HSCI Skin Program.

Restoring vision loss with cell therapy

The cornea is regenerated by stem cells that reside in the adjacent layer, called the limbus. In patients with limbal stem cell deficiency (LSCD), the cornea can become scarred and opaque, leading to vision loss.

Frank, along with his colleagues Natasha Frank, M.D. and Bruce Ksander, Ph.D., has spent the past few years figuring out the best way to identify limbal stem cells and isolate them. They have zeroed in on ABCB5, a protein on the cell surface that they found can be used as a marker for the stem cells.

“In mice without ABCB5, we saw that the cornea had developmental abnormalities. In mice with ABCB5, the protein was present only in a select subset of cells in the limbus,” said Frank.

“That suggested to us that the subset of ABCB5-positive cells represented the stem cells that repair the cornea – which is exactly what we were looking for.”

Indeed, when the researchers isolated and transplanted limbal cells in mice, only the ABCB5-positive ones regenerated clear corneas.

An alternative source of repair cells

Frank and his colleagues have also identified a second source of ABCB5-positive cells.

“Skin cells with ABCB5 normally contribute to skin development. But if we isolate ABCB5-positive cells from skin and put them in the context of an eye with LSCD, they appear to help repair corneal wounds – just like those from the corneal limbus,” explained Frank.

The researchers are now translating their findings to the clinic:

“Now, we are investigating whether ABCB5-positive cells — derived from either the corneal limbus or the skin — can be developed as a cellular therapy for LSCD,” said Frank. “The ABCB5-positive cells we derived from skin are already being evaluated in clinical trials for safety and efficacy in wound healing.”

Self-donors and stem cell banks

LSCD can affect one or both eyes in patients. Accordingly, Frank envisions two strategies for ABCB5-positive cell therapy: self-donors and stem cell banks.

In situations where only one eye is affected, the goal is to isolate ABCB5-positive cells from the other eye, then multiply them and transplant them into the affected eye to restore vision. In this case, the patient would be a “self-donor” of limbal stem cells.

In the majority of patients, though, both eyes are affected – that’s because LSCD is typically caused by trauma such as burns. There are no limbal stem cells left that can be isolated from the patients to grow and transplant back.

For this group of patients, Frank wants to build a repository of donor ABCB5-positive cells.

“We aim to isolate ABCB5-positive cells from the limbus of donors, grow them up in laboratory cultures to get sufficient numbers of cells, then store the purified stem cell product in a biobank,” he explained.

The donor cells would be categorized by their immune system genes, to ensure a close match between the donor and patient. Just like in organ transplantation, the goal is to minimize the chance of transplant rejection by the patient’s immune system.

Frank believes that in general, the chance of immune rejection might be lower for this type of cell therapy than the typical organ transplant: “The central part of the cornea is ‘immune-privileged’, so it’s possible that immune cells can’t get in there to react with cells from a different donor.”

From HSCI Seed Grant to clinical development

Although Frank and his colleagues are currently developing ABCB5-positive cells for therapeutic use, their research leading up to this stage has had its fair share of twists and turns.

“We didn’t start off by knowing what a limbal stem cell was, then searching for a molecular marker expressed on it,” said Frank. “We first found the ABCB5 molecule, and by studying the cells upon which it was expressed, we discovered that they have stem cell characteristics.”

In other words, Frank and his colleagues did not start their project with a specific translational plan; rather, while studying the ABCB5 molecule, they realized that it had therapeutic applications.

“HSCI funded our early work, before the National Institutes of Health became interested in funding this project,” said Frank.

One of the goals of HSCI Seed Grants, like those awarded to Frank and his colleague Natasha Frank, M.D., is to support early-stage research. By promoting high-risk, high-reward research, HSCI ensures that scientists with innovative approaches have the opportunity to help patients.

Read about the HSCI Skin Program

Information for patients: ISSCR