UAlbany scientists explore new molecular tool to treat retinal degenerative disease

Millions of people in the United States are living with reduced eyesight due to a retinal degenerative disease. These can include any of a range of medical conditions affecting the retina—a structure at the back of the eye that captures light and sends signals to the brain to facilitate sight. In these diseases, the cells that make up the retina gradually break down, leading to vision impairment.

Symptoms of retinal degenerative diseases can include vision loss, difficulty seeing in low light, impaired color vision, peripheral vision loss and difficulty distinguishing between objects of similar shades or colors. These diseases are most commonly observed in older individuals; however, genetic and hereditary forms can affect individuals at any age.

University at Albany scientists at the College of Arts and Sciences' RNA Institute, in collaboration with a research team from the University of Buffalo's Jacobs School of Medicine and Biomedical Sciences, have received a four-year, $1.8 million grant from the National Eye Institute to explore a new molecular tool for treating retinal degenerative disease.

At the center of the project is a "hammerhead ribozyme"—an RNA molecule that has been engineered to catalyze a targeted chemical reaction that cuts a messenger RNA (mRNA) strand at a specific location. By cutting the portion of genetic code in the eye that contributes to vision impairment, the research could potentially slow down or halt the progression of various diseases that affect sight. This approach could help preserve retinal function and mitigate vision loss.

"What makes this particular hammerhead ribozyme special is its speed," said co-investigator Ken Halvorsen, a senior research scientist at the RNA Institute. "It is unusually adept at binding and cutting target mRNA sequences quickly, compared to other ribozymes embedded in restrictive scaffolds, which are used for similar applications yet operate at a slower rate.

"My lab will use a combination of biophysical approaches to determine the thermodynamics, kinetics and mechanistic changes involved in ribozyme binding, substrate cleavage and ribozyme release—to help us understand how this type of hammerhead ribozyme is able to operate so quickly. Our ultimate goal is to improve the efficiency of the ribozyme as it moves along the path toward clinical use."

Part of the study aims to establish rules for designing improved ribozymes. By learning how to use hammerhead ribozymes to manipulate RNA in retinal cells, the team hopes to be able to apply these rules to RNA in other cell types to treat various diseases affecting different systems in the body.

"The goal of this project is to provide new therapeutics to treat retinal degenerations, (e.g., autosomal dominant retinitis pigmentosa) due to human rhodopsin mutations," said co-investigator Jia Sheng, associate professor in the Department of Chemistry and the RNA Institute. "Using our expertise in RNA chemical biology, we will design and synthesize new hammerhead ribozymes that can bind and cleave target pathogenic messenger RNAs to block these gene expressions. In addition, we will conduct structural studies to explore their working mechanisms and provide new guidance for future drug design and optimization."

RNA Institute Research Scientist Sweta Vangaveti uses molecular modeling and simulations to study how diseases operate at the cellular level, and how RNA-based therapeutics can affect disease progression. In this study, Vangaveti will develop molecular simulations to illustrate the atomic-level structural changes that take place between the hammerhead ribozymes and the target genetic sequences as the team tests new versions of the ribozyme.

"In the process of developing new drugs, experiments done in the lab can tell us whether a newly developed therapeutic is working or not; however, figuring out exactly how it works and how to make it better are both time and resource intensive," said Vangaveti, a co-investigator on the project. "That's where computer models come in. They are like little movies that show how molecules behave. This helps us determine what compounds may or may not be effective at treating a disease, without having to manufacture every possible iteration of the compound.

"Here, we are focusing on the hammerhead ribozyme—which holds great promise for therapeutics, yet the molecular traits that account for its efficacy remain unknown. By studying the hammerhead ribozyme with our computer models, accompanied by observations from lab experiments, we hope to find out how the hammerhead works, how to expand the pool of genetic sequences that it can target, and how we can engineer it to make it even more effective for biomedical applications."

"This is one of the most 'translational' projects our lab has ever worked on, so I'm excited about the possibility that our work in understanding the activity of the hammerhead ribozyme could directly lead to improvements in a therapeutic that may be brought to clinical use," said Halvorsen. "It's also interesting to work with Dr. Jack Sullivan at Buffalo, a practicing ophthalmologist, because the science and technology we are working on will directly connect with real-world health outcomes."

Provided by University at Albany