Possible Second Generation Cornea Crosslinking Treatment

July 2014

Many patients with keratoconus have benefitted from cornea crosslinking with riboflavin and UVA (CXL), but there is still room for improvement in this treatment. A second generation crosslinking method is being developed that may expand the range of patients that can be treated. For safety reasons, current CXL protocols cannot be used to crosslink thin corneas, defined as those less than about 400 µm (1/60th of an inch) thick. This is a problem because during progression of keratoconus, the cornea becomes thinner as the cornea stretches forward. Consequently, CXL is unavailable to the many patients with thinned corneas.

Recently, a novel crosslinking method was reported that might overcome this barrier to treatment of thin corneas. In laboratory studies, researchers have shown that applying an FDA-approved dye to the cornea and then exposing the cornea to green light for a few minutes increased the stiffness of the cornea to the same level as produced by CXL. An important feature of this new method, which is called RGX, is that the dye remains near the surface of the cornea where it absorbs the green light and produces the crosslinks that stiffen the cornea only near the cornea surface. (shown below)


Because of this specific localization of the dye, the same amount of stiffening occurs in thin as in normal thickness corneas. In addition, a normal thickness cornea is not needed to absorb the activating UV light as is required for CXL. These results underlie the potential for RGX to be able to treat the thin corneas of many keratoconus patients.

RGX is similar to CXL in the way it works to stiffen corneas, but there are some important differences. The dye used for RGX, Rose Bengal, has been used for many years by ophthalmologists to detect corneal abrasions and is considered to be a safe dye. Rose Bengal strongly absorbs green light, which leads to a short treatment time. (shown below)


A total time of less than 15 minutes is needed for dye application and light exposure to stiffen the cornea. In addition, studies have shown that the RGX treatment does not kill the cells that live in the part of the cornea that is crosslinked whereas CXL destroys these cells, a possible advantage of the RGX treatment.

These results indicate that RGX has the potential to safely crosslink thinner corneas. Further work is required to translate these laboratory investigations to clinical application, and the investigators have recently taken further steps toward this goal. Studies in experimental animals have now demonstrated that RGX produces the same cornea stiffening as they had reported for studies using isolated eyes. Also, in studies that followed the eyes for up to one month after RGX, no damage to the retina or iris was detected suggesting that the level of green light used for RGX is safe. Additional investigations to optimize RGX and ensure its safety are planned.

The RGX treatment evolved from previous applications of Rose Bengal and green light for sealing surgical and traumatic corneal wounds as well as for repair of skin, peripheral nerve, blood vessel and tendon damage. For these repairs, collagen-to-collagen crosslinks are formed between tissue surfaces to produce an immediate, water-tight seal.

The research at Massachusetts General Hospital is lead by Irene E. Kochevar, PhD, a member of the Wellman Center for Photomedicine and is in collaboration with Samir Melki, MD, of the Boston Eye Group.

Cherfan D, Verter EE, Melki S, Gisel TE, Doyle FJ, Scarcelli G, Yun SH, Redmond RW, Kochevar IE. Collagen cross-linking using Rose Bengal and green light to increase corneal stiffness. Invest Ophthalmol Vis Sci, 2013;54(5):3426-33.

irenekochevarIrene Kochevar, PhD is Professor of Dermatology, Harvard Medical School with her research laboratories in the Wellman Center for Photomedicine at the Massachusetts General Hospital. Her research focused for many years on fundamental mechanisms for UV and photosensitized oxidative stress in cells. More recently, Dr. Kochevar invented with Dr. Robert Redmond a light-activated protein crosslinking technology for tissue repair that has been applied to many tissue as well as for stiffening cornea as a possible treatment for keratoconus.