Next time you look into a mirror, look closely at one of your eyes. As you look at the clear portion, the cornea, then the white section, the sclera, have you ever wondered why there is such a clear line of demarcation? Have you ever thought about how the cornea, the only organ in your body without a blood supply, keeps itself transparent and healthy for decades?
The limbal stem cell (LSC) is the answer to these questions. The LSCs create a fine line of cells separating the sclera from the cornea. With a little help from the deep basement cells of the cornea (the cells deep within the clear part of the eye), they repopulate the cornea on a continual basis to maintain the health and transparency of the cornea.
About 30 people per million population develop a deficiency of the LSCs for a variety of reasons, including congenital diseases, inflammatory diseases, thermal and chemical burns (in particular alkali injuries), trauma from repeated surgical procedures, and chronic contact lens irritation. When there’s a shortage of LSCs, the barrier between the cornea and conjunctiva is more easily breached, so the white, opaque tissue from the conjunctiva can invade and, in some cases, cover the clear cornea. Symptoms include chronic irritation, photophobia, unstable tear film layer, erosion of the cornea, neovascularization of the cornea, cornea thinning and ulcers, blurring, and even blindness.
Current treatment strategies in the U.S. include removing any source of ongoing trauma, along with a variety of local treatments, such as topical steroids. Transplants of amniotic tissue have been used with varying degrees of success.
Another approach is to transplant LSCs from an unaffected area in the bad eye or from the opposite eye. But LSC transplants have typically required a rather large supply of LSCs, and the eye can be damaged at the donor site.
Some hospitals specializing in diseases of the eye have tried to create a “homebrew” approach to culturing and multiplying donor stem cells and transplanting them, but this approach has been limited to a few hospitals and lacks consistency.
All of this may change soon. Although not yet approved by the FDA, its European equivalent has just approved the first stem cell therapy for limbal stem cell deficiency. The treatment, called Holoclar, consists of a tiny transparent sheet of 300,000 to 1.2 million viable autologous human corneal epithelial cells expanded in cell culture and includes an average of 3.5% LSCs. It comes in a circular transparent sheet of tissue ready for transplantation onto the affected eye.
Holoclar replaces the damaged cornea and, according to the European Medicines Agency, “creating a reservoir of LSCs for continuous regeneration of the epithelium.” Holoclar is indicated for use in ocular burns regardless of whether the deep stromal area of the cornea is damaged. If deep stromal injury has occurred, keratoplasty (removal of damaged deep cornea tissue) may be required along with the Holoclar transplant. Holoclar was not approved for use in genetic disorders that result in LSC deficiency.
The Holoclar procedure involves taking a very small biopsy from the patient needing the transplant, stimulating proliferation of the cells contained in the biopsy specimen using cell-growth factor, and then preserving the “sheet” of tissue by cooling it to low temperatures so it can be stored and eventually transplanted. People talk a lot about new frontiers in medicine, but limbal stem cell transplantation truly is a breakthrough.
One worry with stem cell technology is the tissue may have tumorigenic properties. As a safeguard, Holoclar’s developers tested the chromosomal characteristics of cells in the tissue for stability. Other tests proved that there was no significant immunogenicity, that the cells did not metastasize to other sites in the body, that the cells were not toxic in any sense of the word.
Holoclar was developed by an Italian company, Holostem Terapie Avanzate, a spinoff from the University of Modena. It was studied in 133 people in two studies that were neither randomized nor controlled. Because most of the people studied had limbal stem cell deficiency for many years (87% for more than five years), a pre-post analysis methodology was used to measure endpoints. The two studies differed slightly, but suffice it to say they both included subjects with moderate and severe corneal neovascularization, epithelial defects, corneal opacity of varying degrees, and a potpourri of symptoms. Their vision was poor and limited to counting fingers, detecting hand movements, or perceiving light.
Results were remarkable. Overall “success of transplantation” occurred in 72% of patients and in 92% of those who underwent repeated Holoclar treatment. One year after the procedure, corneal neovascularization changed from a score of “moderate-to-severe” to “moderate-to none” in roughly 3 in 4 patients and epithelial defects were rated at the “trace or none” level in a large majority (84%).
The effects on vision were a little less impressive. Almost half of those who received the transplant said their vision improved. A subgroup analysis demonstrated a much larger percentage (83%) of those without stromal scaring reported improved vision, a finding that may eventually factor into coverage decisions.
The European regulators concluded that in most patients, Holoclar enabled restoration of a stable, intact corneal epithelium with resolution of epithelial defects and regression of corneal vascularization and absence of “conjunctivalisation”—the migration of cells from the conjunctiva into the cornea that can, in severe cases, lead to blindness. Vision and ocular symptoms also improved, and the chance for subsequent successful keratoplasty in patients with deep stromal scarring increased. The regulators noted that mild-to-moderate adverse drug reactions (ADRs) were common, although many were self-limited and some related to the ancillary topical steroid used after surgery to prevent swelling. Overall, the rate of serious ADRs was low, with only three serious ADRs being judged as related to Holoclar.
Holoclar is eventually likely to find its way across the Atlantic. It could benefit thousands of Americans who have had corneal and conjunctival damage from burns or trauma.
Holoclar also demonstrates how our Old World colleagues can sometimes be a step ahead of us in the New World in creating Tomorrow’s Medicine!