R01EY031894

NeuroEbola - Summary

Ebola viruses (EBOV) are among the deadliest pathogens known to man, with a case fatality rate of 25-90% depending on the outbreak. For the first time, monoclonal antibodies ZMapp, MAb114, REGN-EB3, and remdesivir (an inhibitor of viral RNA synthesis) were used, improving survival rates in Ebola Treatment Units (ETU) during the ongoing outbreak of Ebola Virus Disease (EVD) in Congo-Kinshasa. Despite treatments, 34% of EVD survivors experienced eye complications. In addition, they had lower mean (SD) Mini-Mental Test Examination (MMSE) scores, i.e., 25 (5.5), relative to controls 29.9 (0.6) (p < 0.01). Women performed poorly, 24.8 (5.9), relative to men 28.4 (3.2) (p < 0.01). The odds of depression were higher in EVD survivors (OR: 14.9, 95% CI: 4.4-50.1), mostly in women (OR: 4.4, 95% CI: 2.1-9.6). Intriguingly, MMSE deficit in women was associated with higher initial EBOV viral load (OR: 0.84, 95% CI: 0.73-0.98, p = 0.03, for one-unit increase in CTXPTNP; lower CTXPT = higher viral load) after adjustment for age and depression status. EBOV persisted in breastmilk, wet preps, and semen for several months after acute EVD.

We propose to test the hypothesis that the occurrence of neuroophthalmologic sequelae is dictated by the initial and/or persistence of EBOV viral load with discernable IgG responses and/or a persistent inflammatory state driven by elevated cytokines and immune cell activation. This will be addressed by the following specific aims:

Aim 1: To contrast neuro-ophthalmologic deficits (spectrum & extent) found in confirmed EVD survivors to relevant profiles seen in their IgG+ but EVD-free close contacts, and IgG- controls (n = 90 per group). In Aim 1A, study participants will have longitudinal (0, 6, 12, 24, 36, and 48 month-time-points) assessments of neurocognition using the computerized Test of Variables of Attention (auditory and visual), the Test of Attentional Performance, and CogState for nonverbal cognitive skills. In Aim 1B, they will undergo psychophysical tests for visual acuity, contrast sensitivity, color vision, and visual field, as well as spectral domain-optical coherence tomography to elucidate structural biomarkers of disease within visual pathways.

Aim 2: Differences in levels or overabundance of neuroophthalmologic outcomes found in Aim 1 are mediated by EBOV viral load or persistence, anti-EBOV IgG, alterations in levels or activation status of circulating immune cells, and/or proinflammatory cytokines.

Aim 3: Enhance capacity in neurocognitive assessments, ophthalmologic evaluations, and EVD immunoprofiling and molecular biology (RT-PCR). Gaps of knowledge to be filled include a lack of understanding of (1) EBOV persistence, (2) long-lasting immune dysregulation, (3) IgG positivity with no overt EVD symptoms, all in the contexts of post-EVD treatment.

The overall goal of the proposed work aligns with the global health mission of the NIH while integrating the institute-specific missions of FIC, NEI, NIAID, NINDS, and the Office of Disease Prevention.

Oregon Health & Science University

1) TO SUPPORT EYE AND VISION RESEARCH PROJECTS THAT ADDRESS THE LEADING CAUSES OF BLINDNESS AND IMPAIRED VISION IN THE U.S. THESE INCLUDE RETINAL DISEASES, CORNEAL DISEASES, CATARACT, GLAUCOMA AND OPTIC NEUROPATHIES, STRABISMUS, AMBLYOPIA, AND LOW VISION AND BLINDNESS REHABILITATION. 2) TO INCREASE UNDERSTANDING OF THE NORMAL DEVELOPMENT AND FUNCTION OF THE VISUAL SYSTEM IN ORDER TO BETTER PREVENT, DIAGNOSE, AND TREAT SIGHT-THREATENING CONDITIONS, AND, TO ENHANCE THE REHABILITATION, TRAINING, AND QUALITY OF LIFE OF INDIVIDUALS WHO ARE PARTIALLY-SIGHTED OR BLIND. 3) TO SUPPORT A BROAD PROGRAM OF BASIC VISION RESEARCH THROUGH GRANTS AND COOPERATIVE AGREEMENTS, TO ENCOURAGE HIGH QUALITY CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS, OTHER EPIDEMIOLOGICAL STUDIES, AND HEALTH SERVICES RESEARCH, TO ENCOURAGE RESEARCH TRAINING AND CAREER DEVELOPMENT IN THE SCIENCES RELATED TO VISION, AND TO SPONSOR SCIENTIFIC WORKSHOPS IN HIGH PRIORITY RESEARCH AREAS TO ENCOURAGE EXCHANGE OF INFORMATION AMONG SCIENTISTS. 4) SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENCOURAGE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.867 - Vision Research

National Eye Institute (NEI) [HHS - NIH]

Oregon United States

State-Wide

Global Brain and Nervous System Disorders Research Across the Lifespan (R01 Clinical Trials Optional) (PAR-18-835)

Amendment Since initial award the End Date has been shortened from 07/31/26 to 07/31/25 and the total obligations have increased 21689% from $10,000 to $2,178,941.