mRNA-based Therapy for Proliferative Vitreoretinopathy

A serious condition that occurs as a result of trauma to the eye or retinal detachment, proliferative vitreoretinopathy (PVR) is characterized by abnormal scar tissue that forms on the retina. Rather than the original injury to the eye, it is this pathologic scar tissue response that can lead to blindness in patients.

Currently, the only treatment for PVR is vitreoretinal surgery, which, ironically enough, carries with it a higher risk of exacerbating any existing PVR. “We try to peel the scar tissue off of the retina,” explains Leo Kim, Monte J. Wallace Ophthalmology Chair in Retina at Massachusetts Eye and Ear. “One of the most concerning risks [with vitreoretinal surgery] is damage to the retina while removing the scar tissue. In the setting of PVR, the rate of recurrent PVR is rather high up, to 30 percent.”

Seeking to address the current scarcity of non-invasive treatment options for PVR, Kim and his Mass Eye and Ear-based team – in partnership with biopharma firm, CureVac – have been researching the potential of a new mRNA-based therapy that could potentially be used to treat PVR. “The therapy works by delivering mRNA into cells that are involved in forming scar tissue, using specialized carriers that package the RNA, increasing its uptake and maintaining its integrity as it is delivered to the cells,” says Kim.

The Science Translational Medicine report, published in November 2024, highlights the potential of this innovative new therapy for regulating RUNX1 – a gene that is involved both in the formation of scar tissue and abnormal blood vessels in several retinal diseases, including PVR.

Regarding the safety and efficacy of this novel mRNA-based therapy, Kim notes that the team did not observe “any significant inflammatory responses or significant pathological changes within the eye as a result of the therapy.” He adds that in the preclinical models used by the team, significant improvement in PVR severity was seen in the study’s rabbit model, which used patient-derived cells to model the condition. Similarly, in a mouse model of laser-induced choroidal neovascularization, it was noted that there was “significant inhibition of leakage and lesion growth” when employing this mRNA-based approach, suggesting that this technology could indeed be adapted for other ocular conditions.

Given these findings, the team are hopeful that their proof-of-concept research could encourage further studies into this treatment being used for other retinal diseases. “As a therapeutic target, RUNX1 was first discovered by our lab in patient-derived membranes from patients with proliferative diabetic retinopathy,” Kim explains. “Subsequently, our laboratories have implicated RUNX1 in many forms of ocular neovascularization, such as choroidal neovascularization as found in wet AMD, corneal neovascularization, retinal neovascularization as found in PDR, and retinopathy of prematurity.”

He believes that one of the main challenges now will be in attempting to extend the durability of mRNA within the eye, observing, “We had to dose the eyes relatively frequently within our models, suggesting limited durability of mRNA. I think we need to overcome this by figuring out ways to extend the ability of these molecules to produce therapeutic protein for extended periods of time.” Kim also considers proper dosing to represent another major challenge of transitioning the therapy from preclinical to clinical trials. “We have observed that the RUNX1-Trap does not follow conventional behavior associated with dose response curves observed with small molecules,” he says. “Thus, finding a dose that facilitates the intended therapeutic effect without exacerbating any pathological outcomes later on is going to be a critical aspect for success moving forward.”