ABSTRACT
AIMS: This study's objective was to evaluate the tolerance and safety of a new ophthalmic solution based on ReGeneraTing agent (RGTA) technology in a pilot noncontrolled exploration on compassion use for corneal ulcers and severe chronic dystrophies resistant to the usual treatments. RATIONALE: RGTAs are large biopolymers engineered to replace heparan sulfates specifically bound to matrix proteins and growth factors destroyed after a lesion has occurred. The RGTA-bound proteins are protected from proteolysis and this allows the extracellular matrix microenvironment to restore its original proper organization. The initial endogenous signals needed for tissues to regenerate are back on the restored matrix. They are expected to trigger the natural onset of events, signaling cells to migrate and multiply with the cascades and equilibrium found in tissue homeostasis. RGTA-induced matrix therapy is a possible alternative to cell or gene therapy in regenerative medicine. In a rabbit preclinical model of alkali-induced severe corneal ulcers, a single instillation of RGTA ophthalmic solution was found sufficient to enhance speed and quality of healing, restoring an almost normal corneal histology after only 1 week. These data prompted us to initiate this study. PATIENTS AND METHODS: Eleven eyes from ten patients were included in this study. All patients had severe dystrophic cornea or painful corneal ulcers rated over 50 on the VAS pain scale ranging from 0 to 100 and had undergone unsuccessful treatments. The RGTA ophthalmic solution was administered by the investigator during each weekly consultation as a single drop over 1 month. Tolerance and efficacy were judged on subjective criteria based on pain evaluation and functional inconvenience as well as on objective clinical criteria through a complete ophthalmic examination at days 3, 7, 14, 21, 28 and after 2 and 3 months from the beginning of the treatment. RESULTS: The study was conducted to completion for all patients included at the beginning. Tolerance was excellent both locally and generally: no uneasiness during instillation, no worsening of the initial pathology, no occurrence of ocular inflammation or increase in ocular pressure, and no general side effects were observed. In addition, we observed a noticeable analgesic effect, increasing with time and instillations, but pain reappeared in the majority of cases as treatment ended. The mean visual analog scale pain score was 72.73 +/- 7.86, it decreased significantly with the first drops of treatment. After 1 month, the mean visual analog scale pain score was 32+/-15.49, then it increased after the end of the treatment, confirming the link between the effects observed and the treatment. Efficacy on keratitis was moderate but with an overall tendency toward improvement. The initial Oxford Score was 3.37 +/- 1.06. After 1 month, it decreased significantly to 1.57 +/- 0.97 and then it rose again after the end of the treatment. As for corneal ulcers, of the five cases included, four healed during the protocol. Two reversed when the treatment stopped, two healed without reversion at the last follow-up visit. The last case was characterized by stem cell deficiency and no improvement was noted. It is important to keep in mind that these ulcers were all resistant to usual therapies. CONCLUSION: This RGTA ophthalmic solution is the first matrix therapy product in ophthalmology. The RGTA OTR4120 was used in treating chronic and severe corneal dystrophies as well as corneal ulcers resistant to usual treatments. It was very well tolerated with no side effects. It significantly reduced pain and favored corneal healing in almost all corneal ulcers. Weekly instillation of a single drop seems insufficient and these very promising data need to be confirmed on a larger population in a controlled trial with more adapted dosages. Based on these preliminary data, a RGTA-based matrix therapy product may be a very innovative solution to unresolved pain and corneal surface healing problems.
