Preclinical studies show mRNA-based therapy is effective for blinding conditions

“This treatment is the first to deliver mRNA-based therapy inside the eye,” said study co-senior author Leo, the Monte J. Wallace Professor of Ophthalmology in the Retina at Massachusetts Iron and Ear. said A. Kim, MD. “We were pleasantly surprised that this approach could also be used intraocularly without causing excessive inflammation. I hope it will be a pioneer.”

PVR is scar tissue that commonly forms within the eye after eye trauma and can cause the retina to shrink and detach. This pathological scar tissue reaction, rather than the eye damage itself, can lead to blindness.

In a new paper, researchers detail preclinical studies using mRNA as an eye treatment. Messenger RNA (mRNA) is an essential part of every cell in the body. Cells copy a gene's code into pieces of RNA, and these RNAs act as messengers that carry the genetic code to ribosomes, which use it to make proteins. The mRNA strand can code for any protein, even those that are not in the cell's genome. Once introduced into cells, cellular machinery converts these mRNAs into proteins. Proteins make up the structure of cells and help cells perform their functions. They can also turn other genes on or off.

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

Researchers developed and studied the effectiveness of different mRNAs encoding proteins related to scar tissue formation to see which ones might be useful as treatments. To develop a treatment for PVR, researchers targeted a protein called RUNX1, which regulates the expression of a gene that turns eye cells into scar tissue. Early in their careers, Dr. Kim and study co-senior author Joseph Arboleda Velazquez, M.D., Ph.D., discovered that RUNX1 was involved in two processes seen in several retinal diseases: the formation of abnormal blood vessels called aberrant angiogenesis. and found to be involved in scar tissue. or fibrosis. In PVR and other diseases, genes controlled by RUNX1 are overexpressed in the eye, causing scar tissue and abnormal blood vessel growth.

Researchers initially believed targeting RUNX1 was the best approach, but current technology had limitations. Although mRNA is primarily used to increase protein expression, the problem with PVR was excess RUNX1. A key insight for developing this new therapy was the idea of ​​creating molecules that capture RUNX1 and inhibit its function. This is a strategy known in biology as a dominant-negative inhibitor. These dominant-negative molecules are powerful, and cells cannot easily compensate for their effects.

They settled on an mRNA called RUNX1-Trap. This keeps RUNX1 in the cell's cytoplasm, preventing it from entering the nucleus and turning on a gene that turns the cell into scar tissue. They confirmed that treating cells with this mRNA helped stop the development of scar tissue and abnormal blood vessels in patient-derived cells in laboratory cultures, animal models, and patient tissues in the laboratory.

The researchers believe this study is a proof of concept that suggests the mRNA approach may be useful for PVR and other eye diseases. Limitations of this study include that the experiments were performed in cellular and preclinical models. This approach has not been tested on human subjects. The technique itself may have some limitations, as mRNA doesn't stay in cells very long to make proteins. Therefore, researchers are wondering how long the effects of a single treatment last, or whether patients require multiple doses over weeks or months for treatment to effectively prevent PVR. I don't know if.

Researchers are currently looking at ways to extend the half-life of mRNA so it lasts longer, and how to determine the optimal timing of treatment so that the mRNA enters the eye at the right time. Because RUNX1 is active in other diseases, researchers hope to apply its mRNA system and RUNX1-Trap therapy to treat other retinal diseases, such as wet age-related macular degeneration and diabetic retinopathy. That's what I think.

“We believe that targeting RUNX1 could lead to new treatments for vision-threatening conditions,” said Arboleda-Velasquez, an associate scientist at Mass Eye and Ear. “The same idea of ​​using mRNA to generate dominant-negative molecules could yield potentially effective treatments for other conditions, greatly expanding the potential uses of mRNA. ” added Arboleda Velasquez.

“This study is the result of a tremendous effort by our multidisciplinary team,” said study co-lead author Dr. William P. Miller, a postdoctoral fellow in the Department of Ophthalmology at Harvard Medical School. said. This demonstrates new applications of mRNA technology in ophthalmology across several different fields and has implications for other aspects of medicine as well. ”