July 29, 2022—(BRONX, NY)—Two drugs designed by researchers at Albert Einstein College of Medicine preserved vision in mice that developed retinitis pigmentosa (RP), an inherited eye disease that can lead to blindness and for which no treatments currently exist. The findings, published online on July 21 in Nature Communications, suggest that such drugs might also work against more common retinal diseases.
![Ana Maria Cuervo, M.D., Ph.D.]()
Ana Maria Cuervo, M.D., Ph.D.
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The drugs were specifically designed to boost chaperone-mediated autophagy (CMA), a vital “housekeeping” process that disposes of unwanted proteins in cells but becomes less efficient as people age. Ana Maria Cuervo, M.D., Ph.D., co-corresponding author of the paper, discovered CMA in 1993 and named it in 2000. Dr. Cuervo, who has published more than 200 papers on CMA, is professor of developmental and molecular biology, of medicine, the Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases, and co-director of the Institute for Aging Research at Einstein.
A Fruitful Collaboration
Dr. Cuervo’s research has shown that the decline in cellular cleaning is linked to Alzheimer’s, Parkinson’s, atherosclerosis, and other age-related diseases. For more than seven years, she has worked with her Einstein colleague Evripidis Gavathiotis, Ph.D., to develop drugs that can treat these and other diseases by revving up CMA. Dr. Gavathiotis, a professor of biochemistry and of medicine at Einstein and co-leader of the Cancer Therapeutics Program at the NCI-designated Montefiore Einstein Cancer Center, uses structure-based drug design and medicinal chemistry to create new drug compounds.
![Evripidis Gavathiotis, Ph.D.]()
Evripidis Gavathiotis, Ph.D.
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The collaboration between Drs. Cuervo and Gavathiotis (also a co-corresponding author of the paper) has led to the development of potent drug compounds that selectively activate CMA without disturbing other cellular processes and that are suitable for use in animals. In this study, the scientists evaluated whether two of those compounds could treat RP. They were joined by co-corresponding author Patricia Boya, Ph.D., an eye expert at Centro de Investigaciones Biologicas Margarita Salas, Madrid, Spain.
Nearly a decade ago, Dr. Cuervo and colleagues found that CMA plays a crucial role in maintaining normal protein levels in retinal cells and preventing proteins from accumulating to toxic levels. When they recently analyzed the retinal cells of RP patients, the researchers detected abnormally low levels of a CMA-regulator molecule—a protein specifically targeted by their newly developed drugs. “So it seemed logical to see if our drugs would help against RP,” Dr. Cuervo said. “It’s also the most common inherited disease of the retina, affecting 1 in 3,500 Americans, and there isn’t yet a cure.”
Protecting Retinal Cells and Preserving Vision
In testing their two CMA-boosting compounds on a mouse model of RP, the researchers first established that the drugs were able to cross the blood-brain barrier, upregulate CMA in retinal cells, protect the key photoreceptor retinal cells known as rods and cones from degenerating, and were safe for chronic use: Even when mice were given daily doses of the drugs for five months—equivalent to more than 15 years in humans—no cellular or tissue damage was observed.
Next came the key experiments to assess the drugs’ effect on vision. The RP mice were given daily doses of one of the drugs intraperitoneally (within the abdominal cavity), starting around the time when the death of rod cells is at its peak in these mice (from 18 to 25 days old), followed by the death of cone cells. The mice then received electroretinograms, a diagnostic test that measures the electrical activity of the retina in response to a light stimulus. The electroretinogram results indicated that the drugs had preserved visual function during this critical period.
Our findings in mice strongly suggest that these drugs will be able to help people with RP....
Evripidis Gavathiotis, Ph.D.
Finally, the researchers looked at whether the drugs would work when injected intravitreally, i.e., directly into the jelly-like fluid at the back of the eye—the route that clinicians prefer for administering most eye-related drugs. Mouse retinas were analyzed one week after a single injection of one of the drugs. Compared with mice treated with a control injection, electroretinograms showed that vision in the drug-treated mice had been preserved.
“Our findings in mice strongly suggest that these drugs will be able to help people with RP as well,” said Dr. Gavathiotis. “That’s mainly because the same molecular glitch that depresses CMA activity in mouse retinas—and that our drugs were able to overcome—is also present in the retinal cells of many RP patients. And the fact that the CMA-activating drugs prevented the death of retinal cells suggests they could also help against more common degenerative retinal diseases such as diabetic retinopathy and age-related macular degeneration.”
The paper is titled “Targeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration.” Two Einstein postdoctoral fellows—Raquel Gomez-Sintes, Ph.D., and Qishen Xin, Ph.D.,—led the research efforts.