Newly discovered nanobody may lead to treatment for retinitis pigmentosa

A team of scientists from the University of California, Irvine, believes they have discovered a special antibody that may lead to a cure for retinitis pigmentosa, a condition that causes loss of central vision, as well as night vision and color vision.

The study, Structural basis for allosteric modification of rhodopsin by nanobody binding to its extracellular domain, is published in Nature Communications. The study authors are Arum Wu, PhD, David Salom, PhD, John D. Hong, Alexander Turak, Ph.D., Philip D. Kaiser, MD, PhD, and Krzysztof Palczewski, MD, in the Department of Ophthalmology, Gavin Herbert Eye Institute. , at the University of California, Irvine. The research was conducted in collaboration with Jan Steirat, Ph.D., at Vrije Universiteit Brussels (VUB).

Retinitis pigmentosa (RP) is a group of inherited eye diseases that affect the retina at the back of the eye. It results from the death of cells that detect light signals, known as photoreceptors. There is no known cure for RP, and the development of new treatments for this condition depends on cell and gene therapies.

The UCI researchers targeted their study on a specific molecule that they believe will provide a treatment for rhodopsin-related RP (adRP). Rhodopsin is a major light-sensing molecule in the human retina. It is present in rod photoreceptor cells, and mutations in the rhodopsin gene are the main cause of adRP.

More than 150 rhodopsin mutations can cause retinitis pigmentosa, making it difficult to develop targeted gene therapies. However, due to the high prevalence of RP, there has been a significant investment in research and development efforts to find new therapies.”

Krzysztof Palczewski, Ph.D., Donald Brin Professor, UCI School of Medicine

Although rhodopsin has been studied for more than a century, it has been difficult to tackle the basic details of its mechanism for converting light into a cellular signal.

In this study, the researchers used a special type of antibody derived from llamas, known as a nanobody, which can stop the photoactivation of rhodopsin, allowing it to be examined at high resolution.

“Our team has developed nanobodies that act through a novel mechanism of action. These nanobodies have high specificity and can recognize target rhodopsin extracellularly,” said David Sallum, Ph.D., researcher and project scientist at UCLA School of Medicine. “This allows us to lock this GPCR in the absence of a signal.”

The scientists discovered that these nanobodies target an unexpected location in the rhodopsin molecule, near the site where retinaldehyde binds. They also found that the stabilizing effect of these nanobodies could also be applied to rhodopsin mutations associated with retinal disease, suggesting their use as therapeutics.

“In the future, we hope to include the in vitro development of this initial group of nanobodies,” said Arum Wu, PhD, researcher and project scientist at the UCLA School of Medicine. “We will also evaluate the safety and efficacy of future nanobody gene therapy for RP disease.”

The researchers hope to improve the nanobodies’ ability to recognize rhodopsin from other species, including mice, for which several preclinical models of adRP are available. They also have plans to use these nanobodies to achieve a long-term goal in the field of structural resolution of the major intermediate states of rhodopsin from the inactive state to the fully active state for bonding.


University of California – Irvine

Journal reference:

Wu, A.; et al. (2023). Structural basis for allosteric modification of rhodopsin by tethering the nanobody to its extracellular domain. Nature Communications.

(tags for translation)retinitis pigmentosa

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