Investigating Retinal Capillary Stiffening in DR

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Researchers have identified a new mechanism underlying diabetic retinopathy (DR) pathogenesis, and they hope their finding may eventually help lead to the development of oral medications for early DR manage­ment—treatments that will stem the condition before it progresses.¹ The team includes researchers from Doheny Eye Institute, an independent, nonprofit research organization affiliated with UCLA Stein Eye Institute, in collabo­ration with vision researchers at UC Irvine.

Current treatments for late-stage DR may require laser surgery or repeated eye injections and “they are not effec­tive in many patients,” said Kaustabh Ghosh, PhD, Principal Investigator and Associate Professor of Ophthalmology at David Geffen School of Medicine, UCLA, and Doheny Eye Institute. “Tackling DR at the early stage is being recognized as the preferred approach,” said Dr. Ghosh.

Looking at LOX. Inspired by cardio­vascular research showing that diabetes induces stiffening in large blood vessels, Dr. Ghosh and colleagues wanted to investigate how retinal vascular inflam­mation and degeneration in diabetes might be mechanically regulated.

For their study, published in the journal Diabetes, the researchers aimed to identify the role of a collagen-cross­linking enzyme called lysyl oxidase (LOX) in diabetes-induced retinal capillary stiffening. To do this, they performed atomic force microscopy on retinal capillaries that they had isolated from eyes of both diabetic and nondiabetic mice.

“Using atomic force microscopy, a technique originally developed for physics and materials science research, we first showed that retinal capillaries in diabetic mice become stiffer in the early stages due to increased produc­tion of LOX,” Dr. Ghosh said.

Diabetic mice displayed a two- to threefold increase in stiffness over nondiabetic mice, the researchers reported. And retinal capillary stiffen­ing was found to persist in mice with longer-term diabetes (20-30 weeks in this study).

Exploring prevention of retinal stiffening. Next, the investigators evaluated LOX inhibition as a potential strategy for preventing retinal stiff­ening. They administered oral β-ami­nopropionitrile, a LOX inhibitor, to diabetic mice and assessed its effect on retinal capillary health and contrast sensitivity.

“Importantly, blocking this enzyme using an orally administered drug pre­vented the increase in retinal capillary stiffness in diabetic mice that, in turn, protected these capillaries from degen­eration caused by toxic immune cells,” said Dr. Ghosh.

Blocking this stiffness not only halted retinal capillary degeneration but also prevented the loss of contrast sensitivity, a common early hallmark of DR.

“We were pleasantly surprised to see that diabetic mice treated with the oral drug showed significant protection from this visual defect,” Dr. Ghosh said.

Future research. These findings offer novel insights into DR pathogenesis by pinpointing retinal capillary stiffening as a key target for early management, said Dr. Ghosh.

These new findings provide rationale to develop new, sensitive imaging tech­niques to noninvasively detect subtle changes in retinal capillary stiffness, even before detectable capillary loss, he said.

“Success in this effort could have a huge impact on clinical DR manage­ment in the future,” he said.

—Patricia Weiser, PharmD

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1 Chandrakumar S et al. Diabetes. 2024;73:280-291.

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Relevant financial disclosures—Dr. Ghosh: Na­tional Eye Institute/NIH: S; Research to Prevent Blindness: S; Stephen Ryan Initiative for Macular Research: S; W.M. Keck Foundation: S.

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