One of the missions and goals of ophthalmologists is to support patients with diabetes to ensure that they can maintain good vision throughout their lives. Recently remarkable progress in drugs, surgical instruments, and several imaging modalities has improved treatment of diabetic retinopathy (DR). Availability of optical coherence tomography (OCT) has enabled quantitative evaluation of diabetic macular edema. Furthermore, OCT angiography has allowed performance of angiography in a minimally invasive manner. A paradigm shift in treatment of DR occurred owing to availability of micro incision vitrectomy surgery and anti-vascular endothelial growth factor therapy. Despite such advancements, elimination of blindness in patients with DR is challenging. Ophthalmologists are painfully aware of the importance of an early diagnosis and treatment of DR.
I have conducted research on the ocular circulation for a long time and focused on hypothesis that the retinal blood vessels that become impaired by chronic hyperglycemia may be involved in the DR pathogenesis. Consequently, I found that the retinal circulation is impaired before the DR onset. Based on this theory, I will realize a minimally invasive DR treatment through an early diagnosis of this disease via quantitative evaluation of the ocular circulation. To achieve this, I have initiated new research.
I. Minimizing diabetic retinopathy diagnosis
Retinal blood flow (RBF) measurement facilitates quantitative evaluation of retinal circulation (quantification); enables detection of abnormalities before the onset of DR. Considering this advantage, RBF measurement is used as a minimally invasive tool for an early diagnosis of DR. However, the measurements vary greatly among individuals. Therefore, a new evaluation procedure to diagnose impairment of retinal blood vessels associated with DR is required. The RBF is well-regulated by the interaction with retinal neurons and glia to maintain the retinal tissue demands, referred to as retinal neurovascular coupling (NVC). It has been speculated that impairment of the NVC may precede the onset of DR. If the NVC can be evaluated noninvasively and quantitatively by quantifying changes in RBF, the individual differences can be minimized. We investigated two physiologic provocations, i. e., flicker stimulation (increased blood flow) and hyperoxia (decreased blood flow), to detect minute NVC impairment in DR associated with RBF measurement. We evaluated the RBF over time using laser speckle flowgraphy in murine type 2 diabetes model. Although the RBF does not change in steady state during observation period, the responses of RBF during the physiologic provocations were attenuated in the early-stage retinopathy. This experiment noninvasively and quantitatively detected minute NVC impairment that occurred in the early-stage retinopathy. Electrophysiology and histologic findings also showed that NVC abnormalities may precede retinal neuronal dysfunction in type 2 diabetes. It is my understanding that RBF measurement using physiologic provocations targeting the NVC will enable an early diagnosis and intervention of DR in a minimally invasive manner.
II. Minimizing diabetic retinopathy treatment
To develop a minimally invasive treatment for DR, target molecules, dosage forms, and the drug delivery system should be considered. I have conducted joint research with experts in several fields and evaluated whether the following points have positive effects on DR: 1) use of drugs, 2) use of supplements, 3) a nanoparticle eye drop, and 4) a therapeutic vaccine. We have recently developed a nano-eyedrop of fenofibrate, suppressive effect of which on DR has been confirmed by a large clinical trial. This eyedrop enhances intraocular penetration of fenofibrate, resulting in the achievement of penetration to the posterior segment. Furthermore, it inhibited the impaired NVC in type 2 diabetic animals. These findings confirmed the usefulness of this eyedrop as a treatment for new-onset DR. We also confirmed that administration of sodium-glucose cotransporter 2 (SGLT2) inhibitors, supplements, and prorenin peptide vaccine therapy improved NVC in diabetic animals. Herein, I would like to introduce new minimally invasive treatment strategies for DR based on our new findings.
Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc) 126: 358-387,2022.