KOMM: Eye drops for Hereditary Corneal Vascularization treatment

The aim of this project is to prevent blindness caused by corneal vascularization by reformulating a drug used in cancer treatment from oral to topical treatment (eyedrops). We have identified variants in the platelet derived growth factor receptor beta (PDGFRB) gene in patients who loose vision early in life due to corneal vascularization (ingrowth of blood vessels into the clear cornea). Affected children develop the disease as early as two years of age. PDGFRB is a receptor tyrosine kinase that usually is only activated in certain biological processes, such as wound healing. Activation of PDGFRB is also seen in certain diseases, in particular cancer. The gene variants found associated with this disease cause PDGFRB to be constantly activated. This is a key factor in development of the corneal vascularization. We have shown that an approved drug used in cancer treatment reduce activation of PDGFRB in this condition. This opens up the possibility for precision-based treatment of the patients. We have reformulated this drug from oral to topical eye drops. We have tested the effect, and potential side-effects, of this prototype eyedrop in an animal model of the disease. Over time, the animals developed eyelid changes that complicated interpretation of the findings. The drops had a preventive effect on vascular ingrowth, and mice that were treated after the onset of symptoms improved. Treatment were well tolerated, even after long-term treatment. We have started further studies of efficiency of the drops in another animal model with non-hereditary corneal vascularization. We will offer the drops to patients on compassionate ground.

In the project period we have developed dasatinib eyedrops. We have tested the therapy in an animal model with hereditary corneal vascularization. Some mice develop eyelid changes that made evaluation of prophylactic treatment effect difficult. We have shown that in animals treated after presentation of ocular symptoms, dasatinib eyedrops leads to clinically significant improvement. Further, we have data showing reduced progression of corneal vascularization in mice that did not develop eyelid changes. Commercial assessment showed that the marked for dasatinib eyedrops to treat hereditary corneal vascularization is limited. We are therefore planning to proceed with treatment of patients on compassionate grounds. However, since PDGFRB is implicated also in corneal vascularization of non-hereditary orgin, we have initiated testing of dasatinib eyedrops in a non-hereditary animal model.