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Patroller monocytes as modulators of diabetic retinopathy

Periodic Reporting for period 1 - PAMpeR (Patroller monocytes as modulators of diabetic retinopathy)

Reporting period: 2018-05-16 to 2020-05-15

Our overall goal is to identify mechanisms efficient in the repair of microvessels in diabetes; as the possibility of measuring, and potentially activating such mechanisms could permit us to develop biomarkers of risk, as well as therapeutics to limit the complications of diabetes (DM). Preliminary data indicate that a discrete subpopulation of circulating monocytes, known as patrolling monocytes (PMo), represents an endogenous mechanism that protects and repairs retinal microvessels against diabetes.

In 2010 in Europe, over 3.6 million individuals were affected by DR, and over 500,000 had a severe visual impairment resulting from DM, representing an annual total financial cost to the community of €106,000 per 100,000 inhabitants. Epidemiological data predict a dramatic increase in the prevalence of diabetes in Europe, rising from 55 million in 2010, to over 66 million in 2030. It is reasonable to assume there will be a parallel increase in all its complications, including diabetic retinopathy (DR) the most common complication of DM. In this perspective, it is imperative to develop better means to identify, prevent, and treat DR in its early stages; to develop biomarkers of risk; as well as therapeutics to limit the complications of DM. Notably, the impact and relevance of DR in Europe are such that one of the main goals of IMI 2 - call 1 was to improve and enhance investigation for the discovery of new therapeutic options for DR.

The objectives of this project were to: (1) learn whether the biosynthetic profile of PMo changes in relation to increasing duration of diabetes and evolving retinal vascular damage; and, most importantly, (2) bring the study of PMo to clinical investigation.

In conlcusion, this project helps us expand our knowledge on the mechanisms through which PMo exert their protective activities in microvessels in an animal model of diabetes, and potentially in humans. in addition, this project helps us generate the concept that microvessels respond to the presence and activity of PMo with a biosynthetic program functional to the restoration of vascular wellbeing. Integration of the human findings with the data generated in animals, has the potential to foster the development of new therapeutic interventions for the prevention, and for the treatment of DR.
Data stemming from Obective 1 suggest that PMo are activated by diabetes, and are recruited to the damaged retinal microvessels where they deliver healing activities through an anti-inflammatory, anti-apoptotic, pro-adesive/pro-migratory, and vasculo-protective program. Our findings also suggest that DR does not develop until a specific pro-adesive/pro-migratory molecule is up-regulated on PMo, and that vessel damage becomes apparent only when PMo can no longer be recruited because this molecule is no longer up-regulated. These observations provide for the first time a molecular mechanism to explain the initial latency of vascular lesions in diabetes. The research activities related to Objective 2 (human pilot study) are still ongoing, as more than half of the patients have already been enrolled and studied. to date, we have enrolled 12 subjects, specifically (a) 4 patients with 4-8 years of T1DM duration and no signs of DR (representing the condition in which DM may have begun to induce damage that is however counteracted by repair from PMo, thus preventing DR); (b) 4 patients with T1DM for 20 or fewer years and early non-proliferative DR but no other complications (representing the condition in which PMo may have lost functional specifications critical to their repair activity, thus permitting the development of clinical DR); and (c) 4 age- and sex-matched healthy control subjects. Indeed, the SARS-Covid-19 outburst has represented an important limitation for patient enrolment, and has delayed substantially the study progression. We plan on completing the enrolment of patients within 3-4 months, but this predicted timeline highly depends on SARS-Covid-19, and related internal and external hospital regulations.

The dissemination of results originating from Objective 1 should be accomplished by the end of 2020 via the publication of the manuscript “Patrolling monocytes are recruited and activated by diabetes to protect retinal microvessels” on Diabetes, a highly respected journal in the field. As of August 2020, the Editors have requested a resubmission after minor revision. As subject enrolment related to Objective 2 is still ongoing, we predict that the dissemination of these results will be accomplished by the end of 2021. However, this timeline is highly dependent on how SARS-COVID-19 will evolve. Since we have conducted all the different phases of this project with extreme rigor, we expect that the reulst will be reliable, and therefore will answer the pivotal question whether patrolling monocytes play a role also in human diabetes. Indeed, translating our findings from animal models to humans is necessary in order to progress towards the generation of new interventions for human disease, which represents the ultimate goal of our research.
Data from our group as well as from other researchers strongly support that patrolling monocytes exert their vascular benefits via secreted molecules that act in a paracrine manner. If, as we expect, the combination of results from Objective 1 and Objective 2 will confirm that patroling monocytes protect retinal microvessels against diabetes, the next step will be to identify the endogenous molecules capable of restoring the wellbeing of endothelial cells stressed by diabetes, as those molecules could have the potential to be translated into therapies that can be given exogenously. Great progress has been made in decreasing the impact of diabetic retinopathy as a sight-threatening condition. But retinopathy still occurs as a complication of diabetes more than twenty years into the implementation of intensive glycemic control. This is due in part to the fact that the tools for correcting hyperglycemia are still suboptimal. In addition, we do not have yet available drugs that can be added to antidiabetic treatment to help protect the blood vessels from diabetes. We propose that we can learn from endogenous protective mechanisms, interventions for the retinal vessels. This approach could shield vascular cells from many diverse mechanisms of damage, and therewith lessen the impact of diabetes on retinal microvessels (i.e. retinopathy), resulting in a significant improvement in the quality of life of patients, as well as a substantial reduction of the annual total financial cost of diabetic retinopathy to the community.
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