mRNA therapy shows promise for treating proliferative vitreoretinopathy

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Preclinical research results released by the Massachusetts Eye and Ear, Boston, demonstrate proof of concept that a novel message RNA (mRNA)-based therapy might be effective for treating diseases like proliferative vitreoretinopathy (PVR), a blinding disorder for which there is no currently effective treatment other than other surgeries,¹ according to a press release.

The researchers, led by co-first authors Michael O’Hare, PhD, MSc, William P. Miller, PhD, and Said Arevalo-Alquichire, PhD, are from the Schepens Eye Research Institute, Massachusetts Eye and Ear and the Department of Ophthalmology, Harvard Medical School, Boston. The investigators are working with CureVac, a biopharma company that sponsored the research on this drug.

Leo A. Kim, MD, PhD, the Monte J. Wallace Ophthalmology Chair in Retina at Massachusetts Eye and Ear, commented, “This therapy is the first to deliver mRNA-based treatments inside the eye. We were pleasantly surprised that we could even use this approach inside the eye without causing excessive inflammation. We hope that these early findings can usher in new treatment options for PVR and other eye diseases.”

Scientific basis

The rationale behind the work for using mRNA as a therapy in the eye is that it is an essential part of every cell in the body, according to the press release. The cells copy the code of genes into pieces of RNA that serve as messengers to ferry the genetic codes to the ribosomes that then create proteins. Proteins comprise the cellular structure and help it carry out its functions as well as turn other genes on or off.

In their study, the researchers used cell-based, tissue-based, and preclinical models of PVR and abnormal blood vessel growth to show that mRNA-based therapeutics can be used safely in the eye.

They explained, “We found that, among the candidates tested, RUNX1-Trap (CBFβ-SMMHCΔ95) could be used as a therapeutic agent to reduce cell proliferation in vitro; it also suppressed fibrotic membrane formation in eyes with PVR and aberrant angiogenesis in a laser-induced mouse model of choroidal neovascularization. These findings demonstrate the use of an mRNA to generate a therapeutic protein with dominant-negative properties, a concept that may greatly expand the potential of mRNA-based therapeutics.”¹

In the run-up to this study, the study corresponding authors, Kim and Joseph Arboleda-Velasquez, MD, PhD, an associate scientist at the Massachusetts Eye and Ear, had found that RUNX1 was involved in two disease processes in the retina, ie, aberrant angiogenesis and fibrosis. In PVR and other diseases, the gene that RUNX1 regulates is overexpressed in the eye, resulting in scar tissue and abnormal blood vessels to grow.

The mRNA that the investigators focused on, RUNX1-Trap, holds RUNX1 in the cellular cytoplasm. Because it cannot reach the nuclear, RUNX1 cannot turn on the gene that turns the cells into scar tissue. In their patient-derived cells in a lab culture, an animal model, and patient tissues, the investigators observed that treating the cells with this mRNA stopped scar tissue and abnormal blood vessels from developing, a strategy known as a dominant-negative inhibitor.

The researchers consider this study a proof of concept that suggests that the mRNA approach may be useful for PVR and other eye diseases, according to the press release.

Next steps

This approach has not been tested in humans. A limitation is that mRNA does not stay in the cells for a long period, making the treatment effects unknown as well as the number of treatments needed.

The next step in the research is to develop ways to extend the mRNA half-life so that it can last longer and to determine the optimal timing of the treatment to ensure the mRNA gets in the eye at the right time, the authors explained.

Another hope is that RUNX1-Trap therapy may be used to treat other retinal conditions like wet age-related macular degeneration and diabetic retinopathy.

Arboleda-Velasquez said, “We believe targeting RUNX1 could lead to new therapies for sight-threatening conditions. The same idea of making dominant negative molecules produced using mRNA could result in the generation of potentially effective treatments for other conditions, greatly expanding the potential uses for mRNA.”

Reference

1. O’Hare M, Miller WP, Arevalo-Alquichire S, et al. An mRNA-encoded dominant-negative inhibitor of transcription factor RUNX1 suppresses vitreoretinal disease in experimental models. Sci Transl Med. 2024;16:eadh0994; DOI: 10.1126/scitranslmed.adh0994