A recent study suggests that an innovative mRNA-based therapy targeting the RUNX1 protein could potentially prevent blindness and scarring associated with proliferative vitreoretinopathy (PVR). This condition typically arises from traumatic eye injuries or surgeries like repairing a retinal detachment, and currently, effective treatment options are quite limited, relying mostly on further surgical interventions. Researchers are eager to apply this mRNA method to treat other retinal disorders, such as wet age-related macular degeneration and diabetic retinopathy, as RUNX1 is implicated in various diseases.
A preclinical investigation conducted by researchers at Mass Eye and Ear indicates that a groundbreaking mRNA-based therapy may help avert blindness and scarring from proliferative vitreoretinopathy (PVR) that can occur after retinal surgery or traumatic eye injuries. With no effective treatments available for PVR aside from surgery—often risky and potentially worsening the condition—the findings, published in Science Translational Medicine, highlight the potential of mRNA-based therapies to benefit patients with PVR and related retinal issues.
According to Leo A. Kim, MD, PhD, one of the study’s co-authors and chair of Retina at Massachusetts Eye and Ear, “This therapy is the first to introduce mRNA-based treatments directly within the eye. We were delighted to discover that we could use this method safely without triggering significant inflammation. We are optimistic that these preliminary results may pave the way for new treatments for PVR and other eye ailments.”
PVR is characterized by the formation of scar tissue in the eye, often following trauma, which can lead to retina contraction and detachment. It is this pathological response, rather than the initial injury itself, that can result in vision loss.
The new research paper explains the use of mRNA as a therapeutic agent within the eye through preclinical studies. Messenger RNA (mRNA) is a vital component of all body cells. It serves as a messenger that carries genetic information from DNA to ribosomes, which synthesize proteins from this information. mRNA strands can potentially encode any type of protein, even those not originally present in a cell’s genome. When introduced into cells, the cell machinery translates these mRNAs into proteins, which are crucial for cell structure and function.
In their study, the team utilized cell-based, tissue-based, and preclinical models to investigate the safety and potential of mRNA-based therapies for the eye.
The researchers explored various mRNAs that encode proteins related to scar tissue formation to identify potential therapeutic candidates. They focused on the RUNX1 protein, which modulates the expression of a gene responsible for converting eye cells into scar tissue. Earlier work by Kim and Joseph Arboleda-Velasquez, MD, PhD, revealed that RUNX1 plays a role in two critical processes associated with several retinal diseases: the growth of abnormal blood vessels (aberrant angiogenesis) and scar tissue development (fibrosis). In both PVR and other conditions, the gene regulated by RUNX1 is overactive, leading to the unwanted growth of scar tissue and abnormal vessels in the eye.
Initially, the researchers believed that targeting RUNX1 would be an effective strategy; however, existing technologies were limited. While mRNA is typically used to enhance protein expression, the problem in PVR was an excess of RUNX1. A breakthrough for this experimental therapy was the concept of creating a molecule that would sequester RUNX1 and inhibit its activity—a technique known as a dominant-negative inhibitor. Such dominant-negative molecules are robust and their impact cannot be easily countered by the cells.
The team selected an mRNA known as RUNX1-Trap, which retains RUNX1 within the cell cytoplasm, hindering its entrance into the nucleus, where it would activate the gene responsible for generating scar tissue. The treatment proved effective in laboratory cultured patient cells, in animal studies, and in patient-derived tissues, significantly preventing scar formation and abnormal blood vessel growth.
This study serves as a proof of concept indicating that an mRNA-based strategy could be valuable for addressing PVR and similar ocular conditions. However, there are limitations since the experiments were conducted in cellular and preclinical models, and the approach has yet to be tested in humans. Additionally, the transient nature of mRNA in cells raises questions about the sustainability of treatment effects and whether patients might need repeated doses over time to effectively manage PVR.
The research team is investigating methods to prolong the lifespan of the mRNA to enhance its effectiveness and determine the ideal timing for treatment to ensure the mRNA reaches the eye when needed. With RUNX1 being relevant in various conditions, the researchers also envision expanding the application of their mRNA approach and RUNX1-Trap therapy for other retinal disorders such as wet age-related macular degeneration and diabetic retinopathy.
Arboleda-Velasquez, an associate scientist at Mass Eye and Ear, stated, “Targeting RUNX1 may lead to innovative treatments for conditions that threaten vision. Creating dominant-negative molecules through mRNA could produce effective therapies for a wider range of diseases, significantly broadening the applications of mRNA technology.”
William P. Miller, PhD, a co-first author and postdoctoral fellow at Mass Eye and Ear and Harvard Medical School, remarked, “This study reflects the dedication and collaboration of our team, which includes experts from diverse fields. It showcases unique uses of mRNA technology in ophthalmology and could have implications across other medical areas as well.”