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Mu's Research On Retinal Development Renewed By NIH

Research on retinal development led by Xiuqian Mu, PhD, has been renewed for another five years by the NIH's National Eye Institute.

Published August 30, 2023

The National Eye Institute has approved additional funding for research on retinal development led by Xiuqian Mu, MD, PhD, professor of ophthalmology.

The National Institutes of Health grant is for $2.3 million over five years and represents the third funding cycle of one of Mu's NIH grants through a competitive renewal application.

The renewal funds years 11 through 15 of the grant that originated in 2011. The study is titled "Regulatory Mechanisms for Retinal Ganglion Cell Genesis." 

Seeking Strategies to Treat Various Retinal Diseases

"The retina is a thin neural tissue in our eye and functions to receive visual signals (light) and send them to the brain," says Mu, principal investigator on the grant. "This function is carried out by many cell types, or neurons, in the retina."

"The proposed project studies how one of the cell types, retinal ganglion cells (RGC), is generated during embryonic development," he adds. "This study is aimed at understanding how key regulating proteins (transcription factors) interact with and modify the status of chromatin in the cell and promote RGC differentiation."

Mu points out that retinal ganglion cells are the only cell type connecting the retina to the brain via the optic nerve and are affected in many retinal diseases.

"The findings from the proposed experiments will lead to further insights into the molecular basis underpinning the generation of this important retinal cell type and offer guidance for developing strategies to treat degenerative retinal diseases such as glaucoma," he says.

Revealing Roles of Transcription Factors

During embryonic development, the various retinal cell types all originate from a common pool of retinal progenitor cells (RPCs), although individual cell types are born in distinct time windows, Mu says.

"How individual retinal cell types arise from RPCs is an active field of research, as it is critical to understanding the generation of cellular diversity in the retina and developing therapeutic strategies to treat degenerative retinal diseases," he adds.

Mu notes that many transcription factors involved in the generation of individual retinal cell types have been identified and his lab has made major discoveries in understanding their functions using state-of-the-art technologies.

"Single cell technologies have led to unprecedented progress in discerning the cellular relationships of the different lineage trajectories and the underlying changes in the epigenetic landscape," he adds.

"The roles of individual transcription factors in shaping the epigenetic landscape to drive multipotent RPCs to specific fates are also beginning to be revealed."

RGC Genesis Mechanisms Studied

One of the major findings from the single cell RNA-seq (scRNA-seq) studies is that all the retinal lineage trajectories go through a shared state, namely transitional RPCs (tRPCs), before fate determination, Mu explains.

tRPCs are multipotent and co-express genes involved in the different retinal cell types such as Atoh7 for retinal ganglion cells (RGCs) and Otx2 and Neurod1 for photoreceptors, but how individual cell fates is decided remains unknown, he adds.

"Our long-term objective is to understand the mechanisms controlling RGC genesis," Mu says. "In this application, we propose to address several key knowledge gaps regarding the emergence of the RGC lineage from tRPCs."

"The first is the missing branch of upstream inputs as indicated by scRNA-seq analysis of the Atoh7-null retina. We hypothesize that the some candidate factors fulfill this role by functioning in parallel with Atoh7 to promote RGC genesis."

"The second gap we aim to address is the molecular basis for the specificity of Atoh7 for the RGC lineage. This is based on the fact that multiple proneural bHLH transcription factors are expressed in the retina, but only Atoh7 promotes RGC formation."

Tao Liu, PhD, associate professor of oncology at Roswell Park Comprehensive Care Center, and research associate professor of biochemistry at the Jacobs School, is a co-investigator on the study.

US FDA Declines To Approve Outlook Therapeutics' Eye Disease Drug

Signage is seen outside of the Food and Drug Administration (FDA) headquarters in White Oak, Maryland, U.S., August 29, 2020. REUTERS/Andrew Kelly/File Photo Acquire Licensing Rights

Aug 30 (Reuters) - Outlook Therapeutics (OTLK.O) said on Wednesday the U.S. Food and Drug Administration declined to approve its experimental eye disease drug, in part due to manufacturing issues observed during pre-approval inspections.

The company's shares were down about 78% at 30 cents in premarket trading.

The health regulator's decision marks the latest roadblock for the drug to enter the market, after Outlook Therapeutics last year withdrew its application following an FDA request for additional information.

Outlook Therapeutics said on Wednesday that although the trial for the drug met the goals of safety and efficacy, the FDA cited the need for further confirmatory clinical evidence.

The drug ONS-5010 is under development as an injection for the treatment of wet age-related macular degeneration (AMD) and other retinal diseases.

Wet AMD is a chronic eye disorder that causes blurred vision or a blind spot in the patient's visual field, and is the leading cause of blindness among the elderly.

Outlook Therapeutics had been pinning its hopes on the approval of the drug as the first eye-disease focused version of Roche's (ROG.S) cancer drug Avastin.

Outlook Therapeutics will request a meeting with the FDA to address the issues. The European Medicines Agency is set to begin its review process for the drug, with a decision date expected early next year.

The company's application to the FDA was based on a late-stage trial, which showed the drug improved vision in 41.7% patients who were able to read at least 3 lines or 15 letters, when tested in their ability to distinguish shapes and the details.

Reporting by Sriparna Roy in Bengaluru; Editing by Shounak Dasgupta

Our Standards: The Thomson Reuters Trust Principles.

Retinal Changes Emerge Years Before Parkinson's Disease

People with Parkinson's disease had retinal changes that could be seen with optical coherence tomography (OCT) years before diagnosis, cross-sectional data suggested.

Both incident and prevalent Parkinson's disease were associated with reduced ganglion cell-inner plexiform layer (GCIPL) and inner nuclear layer (INL) thicknesses, reported Siegfried Karl Wagner, MSc, MD, of University College London in England, and co-authors.

People with prevalent Parkinson's disease had thinner GCIPL (-2.12 μm, P=8.2 × 10-5) and INL (-0.99 μm, P=2.1 × 10-4) after adjusting for age, sex, ethnicity, hypertension, and diabetes, the researchers wrote in Neurology.

Incident Parkinson's also was associated with thinner GCIPL (HR 0.62 per standard deviation increase, P=0.002) and thinner INL (HR 0.70, P=0.026).

The study "sets new standards for the role of retinal morphology as potential biomarker in neurodegenerative disease," observed Valeria Koska and Philipp Albrecht, MD, both of Heinrich Heine University Düsseldorf in Germany, in an accompanying editorial.

"It not only corroborates previous studies but also provides new evidence, e.G., a reduced thickness of the inner nuclear layer," Koska and Albrecht wrote. "It fosters our understanding that [Parkinson's] is a systemic disease, which extends beyond dopaminergic neurons and also involves the retina as peripheral part of the central nervous system already at a very early and apparently even presymptomatic stage."

The effect sizes in the study were small and the practical value of using retinal OCT images to identify early Parkinson's with the current protocols and technology in clinical care is limited, the editorialists noted.

"However, with the advent of artificial intelligence, they might prove useful for the development of new multivariable prognostic factors based on combinations of several biomarkers," they pointed out.

In previous studies, retinal OCT has shown promise as a diagnostic aid for mild cognitive impairment and has been studied as a potential biomarker of presymptomatic Alzheimer's disease.

Wagner and co-authors evaluated prevalent Parkinson's disease among people in the retrospective AlzEye cohort in England and incident disease in the prospective U.K. Biobank cohort.

In the AlzEye cohort, 700 individuals had prevalent Parkinson's disease and 105,770 people were controls. Mean age was about 66 and 51.7% were women. The U.K. Biobank study included 50,405 participants with a mean age of 56 and 54.7% were women. In this cohort, 53 people developed Parkinson's disease over an average of 7.3 years.

All participants had non-mydriatic macula-centered OCT imaging. In the U.K. Biobank cohort, researchers included only participants who had retinal imaging at their initial assessment visit (baseline). U.K. Biobank participants who self-reported Parkinson's disease at baseline were excluded from the study.

Parkinson's disease was defined by diagnostic codes. People with diagnostic codes for all-cause dementia were excluded.

In the AlzEye group, people with Parkinson's were older and more likely to be male, hypertensive, and have diabetes. In the U.K. Biobank cohort, adjusted survival analysis showed that age and male sex were associated with incident Parkinson's disease.

In the U.K. Biobank group, the association between thinner GCIPL or INL and incident Parkinson's disease persisted even when participants diagnosed with Parkinson's in the first 24 months after retinal imaging were excluded.

The study had several limitations, Wagner and colleagues acknowledged. The AlzEye cohort did not have detailed clinical information about Parkinson's status, and retinal changes could not be related to disease duration or severity. Because Parkinson's disease was identified by diagnostic codes, some cases may have been missed.

Future studies are needed to determine whether the progression of GCIPL atrophy is driven by Parkinson's brain changes or whether INL thinning precedes GCIPL atrophy, the researchers added.

"I continue to be amazed by what we can discover through eye scans," Wagner said in a statement. "While we are not yet ready to predict whether an individual will develop Parkinson's, we hope that this method could soon become a pre-screening tool for people at risk of disease."

Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer's, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson's, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

This study was funded by Fight for Sight UK, Medical Research Council, U.K. Research & Innovation, the Basque Health Department, and the Wellcome Trust.

Wagner is funded by the Medical Research Council and the Rank Prize. Co-authors reported numerous grants, awards, and fellowships.

Primary Source

Neurology

Source Reference: Wagner SK, et al "Retinal optical coherence tomography features associated with incident and prevalent Parkinson disease" Neurology 2023; DOI: 10.1212/WNL.0000000000207727.

Secondary Source

Neurology

Source Reference: Koska V, Albrecht P "Inner retinal thickness changes in prevalent and incident Parkinson disease: A potential biomarker with prognostic value?" Neurology 2023; DOI: 10.1212/WNL.0000000000207780.

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