Rationale of Basic and Cellular Mechanisms Considered in Updating the Staging System for Diabetic Retinal Disease

M. Elizabeth Hartnett, MD; Ward Fickweiler, MD, PhD; Anthony P. Adamis, MD; Michael Brownlee, MD; Arup Das, MD, PhD; Elia J. Duh, MD; Edward P. Feener, PhD; George King, MD; Renu Kowluru, PhD; Ulrich F.O. Luhmann, PhD; Federica Storti, PhD; Charles C. Wykoff, MD, PhD; Lloyd Paul Aiello, MD, PhD

Ophthalmology Science (Sep 2024)

Rationale of Basic and Cellular Mechanisms Considered in Updating the Staging System for Diabetic Retinal Disease

M. Elizabeth Hartnett, MD,
Ward Fickweiler, MD, PhD,
Anthony P. Adamis, MD,
Michael Brownlee, MD,
Arup Das, MD, PhD,
Elia J. Duh, MD,
Edward P. Feener, PhD,
George King, MD,
Renu Kowluru, PhD,
Ulrich F.O. Luhmann, PhD,
Federica Storti, PhD,
Charles C. Wykoff, MD, PhD,
Lloyd Paul Aiello, MD, PhD

Affiliations

M. Elizabeth Hartnett, MD: Department of Ophthalmology, Byers Eye Institute of Stanford University, Palo Alto, California; Correspondence: M. Elizabeth Hartnett, Byers Eye Institute at Stanford University, 1651 Page Mill Road, Palo Alto, CA 94304.
Ward Fickweiler, MD, PhD: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts; Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
Anthony P. Adamis, MD: Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts
Michael Brownlee, MD: Departments of Medicine and Pathology, Einstein Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York
Arup Das, MD, PhD: Department of Surgery, University of New Mexico School of Medicine, Albuquerque, New Mexico
Elia J. Duh, MD: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Edward P. Feener, PhD: Research Division, KalVista Pharmaceuticals, Inc, Cambridge, Massachusetts
George King, MD: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts
Renu Kowluru, PhD: Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University, Detroit, Michigan
Ulrich F.O. Luhmann, PhD: Roche Pharmaceutical Research and Early Development, Translational Medicine Ophthalmology, Roche Innovation Center Basel, Basel, Switzerland
Federica Storti, PhD: Roche Pharmaceutical Research and Early Development, Translational Medicine Ophthalmology, Roche Innovation Center Basel, Basel, Switzerland
Charles C. Wykoff, MD, PhD: Ophthalmology, Retina Consultants of Texas, Houston, Texas; Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas
Lloyd Paul Aiello, MD, PhD: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts; Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts

Journal volume & issue: Vol. 4, no. 5
p. 100521

Abstract

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Purpose: Hyperglycemia is a major risk factor for early lesions of diabetic retinal disease (DRD). Updating the DRD staging system to incorporate relevant basic and cellular mechanisms pertinent to DRD is necessary to better address early disease, disease progression, the use of therapeutic interventions, and treatment effectiveness. Design: We sought to review preclinical and clinical evidence on basic and cellular mechanisms potentially pertinent to DRD that might eventually be relevant to update the DRD staging system. Participants: Not applicable. Methods: The Basic and Cellular Mechanisms Working Group (BCM-WG) of the Mary Tyler Moore Vision Initiative carefully and extensively reviewed available preclinical and clinical evidence through multiple iterations and classified these. Main Outcome Measures: Classification was made into evidence grids, level of supporting evidence, and anticipated future relevance to DRD. Results: A total of 40 identified targets based on pathophysiology and other parameters for DRD were grouped into concepts or evaluated as specific candidates. VEGFA, peroxisome proliferator-activated receptor-alpha related pathways, plasma kallikrein, and angiopoietin 2 had strong agreement as promising for use as biomarkers in diagnostic, monitoring, predictive, prognostic, and pharmacodynamic responses as well as for susceptibility/risk biomarkers that could underlie new assessments and eventually be considered within an updated DRD staging system or treatment, based on the evidence and need for research that would fit within a 2-year timeline. The BCM-WG found there was strong reason also to pursue the following important concepts regarding scientific research of DRD acknowledging their regulation by hyperglycemia: inflammatory/cytokines, oxidative signaling, vasoprotection, neuroprotection, mitophagy, and nutrients/microbiome. Conclusion: Promising targets that might eventually be considered within an updated DRD staging system or treatment were identified. Although the BCM-WG recognizes that at this stage little can be incorporated into a new DRD staging system, numerous potential targets and important concepts deserve continued support and research, as they may eventually serve as biomarkers and/or therapeutic targets with measurable benefits to patients with diabetes. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Published in Ophthalmology Science

ISSN: 2666-9145 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Ophthalmology
Website: https://www.journals.elsevier.com/ophthalmology-science/

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