UC Irvine researchers discover a nanobody which may lead to treatment for Retinitis Pigmentosa

Newswise — Irvine, CA, August 29, 2023 – A team of scientists from the University of California, Irvine, believe they have discovered a special antibody which may lead to a treatment for Retinitis Pigmentosa, a condition that causes loss of central vision, as well as night and color vision. 

The study, Structural basis for the allosteric modulation of rhodopsin by nanobody binding to its extracellular domain, was published in Nature Communications. Authors of the study were Arum Wu, PhD, David Salom, PhD, John D. Hong, Aleksander Tworak, PhD, Philip D. Kiser, PharmD, PhD, and Krzysztof Palczewski, PhD, in the Department of Ophthalmology, Gavin Herbert Eye Institute, at the University of California, Irvine. 

Retinitis Pigmentosa (RP) is a group of inherited eye diseases that affect the retina in the back of the eye. It is caused by the death of cells that detect light signals, known as photoreceptor cells. There is no known cure for RP, and the development of new treatments for this condition relies on cell and gene therapies. 

UCI researchers have targeted their study on a specific molecule which they believe will provide a treatment for Rhodopsin-associated autosomal dominant RP (adRP). The molecule, Rhodopsin, is a key light-sensing molecule in the human retina. It is found in rod photoreceptor cells, and mutations in the Rhodopsin gene are a primary cause of adRP. 

“More than 150 mutations in rhodopsin can cause Retinitis Pigmentosa, making it challenging to develop targeted gene therapies,” said Krzysztof Palczewski, PhD, Donald Bren Professor, UCI School of Medicine. “However due to the high prevalence of RP, there has been significant investment in research and development efforts to find novel treatments.”

Although Rhodopsin has been studied for over a century, key details of its mechanism for converting light into a cellular signal have been difficult to experimentally address. For this study, researchers used a special type of llama-derived antibody, known as a nanobody, that can halt the process of Rhodopsin photoactivation, allowing it to be investigated at high resolution. 

“Our team has developed nanobodies that work through a novel mechanism of action. These nanobodies have high specificity and can recognize the target rhodopsin extracellularly,” said David Salom, PhD, researcher and project scientist, UCI School of Medicine. “This enables us to lock this GPCR in a non-signaling state.” 

Scientists discovered that these nanobodies target an unexpected site on the Rhodopsin molecule, near the location where retinaldehyde binds. They also found that the stabilizing effect of these nanobodies can also be applied to Rhodopsin mutants that are associated with retinal disease, suggesting their use as therapeutics. 

“In the future, we hope to involve the in vitro evolution of these initial set of nanobodies,” said Arum Wu, PhD, researcher and project scientist, UCI School of Medicine. “We will also evaluate the safety and effectiveness of a future nanobody gene therapy for RP.”

Researchers hope to improve nanobodies’ ability to recognize Rhodopsin from other species including mice, for which several pre-clinical models of adRP are available. They also have plans to use these nanobodies to address a long-term goal in the field of structurally resolving the key intermediate states of Rhodopsin from the inactive state to the fully ligand-activated state.

About the UCI School of Medicine

Each year, the UCI School of Medicine educates more than 400 medical students and nearly 150 PhD and MS students. More than 700 residents and fellows are trained at the UCI Medical Center and affiliated institutions. Multiple MD, PhD and MS degrees are offered. Students are encouraged to pursue an expansive range of interests and options. For medical students, there are numerous concurrent dual degree programs, including an MD/MBA, MD/MPH, or an MD/MS degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Program in Medical Education for Leadership Education to Advance Diversity-African, Black and Caribbean (PRIME LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit https://medschool.uci.edu/

Grant info: 

This research was supported in part by grants from the National Eye Institute (R01EY034519 to P.D.K. and K.P.), the Department of Veterans Affairs (I01BX004939 to P.D.K.) and the National Science Foundation (CHE-2107713 to P.D.K.). The authors acknowledge support from NIH grant P30EY034070 and from an unrestricted grant from Research to Prevent Blindness to the Gavin Herbert Eye Institute at the University of California, Irvine. We acknowledge INSTRUCT-ERIC, part of the European Strategy Forum on Research Infrastructures (ESFRI to J.S.), and the Research Foundation Flanders (FWO to J.S.) for their support for the Nanobody Discovery. Use of beamlines 12-1 and 12-2 at the SSRL, SLAC National Accelerator Laboratory, is supported by the U.S. DOE Office of Science under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health (P41GM103393). This work is based upon research conducted at the NE-CAT beamlines, which are funded by the NIH (P30 GM124165). This research used resources of the APS, a U.S. DOE Office of Science User Facility operated by Argonne National Laboratory under contract no. DE-AC02-06CH11357. This research study was also supported in part by the Japanese Ministry of Education, Culture, Sports, Science, and Technology (18K14662 to K.K.) and (21H04969 toH.K.); by a grant-in-Aid for Scientific Research on Innovative Areas “Non-equilibrium-state molecular movies and their applications (Molecular Movies)” from MEXT, Japan (20H05440 to K.K.), and from the Japan Science and Technology Agency (JST), PRESTO (JPMJPR19G4 to K.K.). The contents of this publication do not necessarily represent the official views of any funding agency.