van Kuijk lab
Role of Zinc in Age Related Macular Degeneration (AMD)
AMD is the leading cause of blindness in the developed world. In association with Dr. Scott McPherson, we have begun to study whether imaging sub-retinal zinc (Zn) can be useful in elucidating its role in the pathogenesis or prevention of AMD and whether this imaging can be a useful biomarker for detecting the earliest stage of AMD in animal models and eventually in humans. Although many genetic and environmental risk factors have been associated with AMD, the earliest cellular changes leading to the disease have not been elucidated. Zinc is the most prevalent metal in the retina, yet its role in both pathogenesis and prevention of AMD is not understood, and in some instances appears paradoxical. Zinc has long been included in dietary supplements designed to limit AMD despite contradictory studies about its efficacy. Conversely, high levels of zinc have been found in drusen, sub-retinal epithelial pigment deposits whose presence in and around the macula is highly correlative with severe AMD, suggesting a pathological role for zinc in AMD progression. To date, the relationship between zinc and AMD has only been explored with epidemiological and cell culture studies. Determining the cause/effect nature of zinc in AMD will require defined animal models. To this end, we have begun to study zinc probes and mouse models that replicate AMD with the goals of 1) Developing an in-vivo assay for drusen in mouse models based on zinc detection that will ultimately lead to the development of a rapid and sensitive clinical assay for human drusen, the hallmark of early AMD and; 2) Determining if gain (or loss) of zinc from retinal cells correlates with known genetic and environmental factors associated with AMD. In this way, we can begin to determine the mechanism(s) by which zinc can be either pathogenic or preventive in AMD.
To date we have identified two highly sensitive, fluorescent probes for zinc detection and have used these in ex-vivo assays to detect drusen in both human and murine tissue and to show changes in zinc in murine retinal pigment epithelial cells associated with aging and light exposure. Further, we have detected drusen in murine retina samples by intravenous (IV) of zinc probe into the mouse followed by direct ex-vivo examination of tissue for fluorescence without additional probe – an important step in developing zinc fluorescence as a clinical assay for drusen detection and early diagnosis of AMD.
Serum Zinc Levels and COVID-19 patient outcomes
Zinc has been shown to be important in immune system development, function, and homeostasis. Zinc deficiency is particularly associated with respiratory infections with the World Health Organization (WHO) estimating that it accounts for 16% of all world-wide respiratory infections. Conversely, zinc supplementation has proven effective in preventing and treating respiratory infections. The obvious link between zinc and respiratory infections has led to both review and new speculation on how zinc could impact COVID-19 pathogenesis infections. Although further study is needed, it has been suggested that zinc can inhibit SARS-CoV-2 directly by blocking the function its cellular receptor the angiotensin-converting enzyme 2 (ACE2) by inhibiting the activity of its papain-like protease domain and by limiting viral replication through inhibition of its RNA-dependent RNA polymerase. That zinc levels could be crucial to COVID-19 outcomes is also suggested by the link between diarrhea and zinc deficiency. Diarrhea has been observed in about 10% of COVID-19 patients and tends to be more prevalent among the most critically ill cases.
While direct studies of zinc in humans infected with SARS-CoV-2 are just beginning, the indirect evidence discussed above suggests it would have a beneficial role. We and other have called for studying the role of zinc in COVID-19 prevention and treatment. We have begun a clinical study to explore whether serum zinc levels correlate with the severity and outcome of COVID-19. Our objectives are to determine if there is a correlation at the time of hospitalization between serum zinc levels and patient condition, and if there is a predictive relationship between serum zinc levels and disease outcomes including the development of critical illness, recovery, and mortality.
Investigate Oral Zinc as a Prophylactic Treatment for Those at Risk for COVID-19. McPherson SW, Keunen JE, Bird AC, Chew EY, van Kuijk FJ. Am J Ophthalmol. 2020 Aug;216:A5-A6. doi: 10.1016/j.ajo.2020.04.028. Epub 2020 May 26.PMID: 32505362
Enhanced detection of sub-retinal epithelial cell layer deposits in human and murine tissue with new zinc detecting probes. McPherson, SW, Roehrich H, Ghosh S, Sada K, Venkateswarulu M, van Kuijk FJ. Investigative Ophthalmology and Visual Sciences. 2018 59(9):364.
Enhanced Detection of Sub-Retinal Pigment Epithelial Cell Layer Deposits in Human and Murine Tissue: Imaging Zinc as a Biomarker for Age-Related Macular Degeneration (An American Ophthalmological Society Thesis). van Kuijk FJGM, McPherson SW, Roehrich H. Trans Am Ophthalmol Soc. 2017 Aug 22;115:T3. eCollection 2017 Aug.PMID: 29021717