RUNX1 for Your Sight

Researchers have found a way to effectively deliver drugs to the back of the eye in preclinical models of proliferative vitreoretinopathy (PVR). The team from the Schepens Eye Research Institute had previously linked transcription factor RUNX1 to the abnormal blood vessel growth in patients with proliferative diabetic retinopathy (1).

Now, the team has built on these findings by packaging the inhibitor into microscopic nanoparticles, which they administered as daily eye drops to rabbits with PVR – a condition which currently lacks an approved medical treatment. The result was a reduced severity of PVR (1). Leo A. Kim, Assistant Professor of Ophthalmology at Harvard Medical School, Mass Eye and Ear Infirmary, Schepens Eye Research Institute, explains. 

How is RUNX1 involved in PVR?
RUNX1 is an important mediator of the epithelial-mesenchymal transition. As the name implies, this is the process by which epithelial cells are transformed into mesenchymal cells, and the conversion of retinal epithelial cells into myofibroblastic cells plays a critical role in PVR. Using patient-derived PVR membranes, we were able to show that RUNX1 inhibition can prevent the formation of these cells.

Why did you choose to study PVR in particular?
We initially identified a key role for RUNX1 in pathologic ocular angiogenesis and proliferative diabetic activity. While we believe RUNX1 inhibition may have the potential to treat pathologic angiogenesis, we chose to focus on PVR because it currently has no approved medical treatment. The standard of care is vitreoretinal surgery, which often fails due to recurrent PVR, especially in retinal detachment cases associated with ocular trauma.  

How and why was the RUNX1 inhibitor packaged into nanoparticles? 
By using a detergent and aqueous phase mixture, we were able to create a nano-emulsion of Ro5-3335, which is a small molecule RUNX1 inhibitor.  One of the issues we had with Ro5-3335 was its relatively low solubility. In other words, if we just used an aqueous vehicle, the Ro5-3335 would precipitate out of the solution. The nano-emulsion was our way to solubilize Ro5-3335 and allow effective delivery inside the eye. 

What were the results of the animal study?
The drops were applied three times a day for two weeks, and we saw a significant reduction in disease severity in a rabbit model of PVR. We measured 2.67 ng/ml of Ro5-3335 within the vitreous in a rabbit eye, suggesting that topical delivery of a RUNX1 inhibitor is feasible. We did not see any adverse effects.

What might this mean for the future of blinding eye disease treatments?
The results in preclinical models suggest the feasibility of RUNX1 inhibition as a topical treatment for a number of blinding eye diseases. As well as PVR, we are hopeful that topical inhibition of RUNX1 could potentially modify other diseases, such as wet age-related macular degeneration or proliferative diabetic retinopathy. 

What’s next?
RUNX1 is a very interesting target – especially for ocular diseases – and may be regulating multiple pathologic pathways and cellular responses. We recently showed TNF-alpha regulation of RUNX1 activity in endothelial cells, suggesting that RUNX1 is responsive to inflammatory cytokines that play a role in a variety of ocular diseases. Our work to date is only the beginning of our understanding of this important molecule.