The ultimate goal of our work is to develop drug strategies for the prevention of diabetic retinopathy. Prevention has been brought within reach by the progressively wider implementation of intensive glycemic control, and we anticipate that the addition of drugs that are effective in pre-emptying the tissue effects of residual hyperglycemia and are safe for long-term administration will make prevention a reality. There are no adjunct drugs usable clinically, and there are no rigorous positive or negative information on the type of drugs that may be effective in the prevention of human diabetic retinopathy. We thus sought to learn from drugs that prevent experimental diabetic retinopathy which molecular processes must be silenced in the retinal vessels in order to prevent the sight-threatening damage induced by diabetes. We tested two drugs with different mechanisms of action (an aldose reductase inhibitor and aspirin at low-intermediate concentrations) reasoning that molecular targets common to the two drugs would identify candidate pathogenic pathways to be investigated further. The experiments showed that, in rats, (i) diabetes changes the expression of multiple genes in retinal vessels, (ii) the TGF-beta pathway was the single functional pathway mostly affected by diabetes, and (iii) the two drugs had private as well as common targets, with the TGF-beta pathway being one of the two common functional targets. Given that overactivity of the TGF-beta pathway could explain much of the vascular histopathology of diabetic retinopathy, and based on additional results documenting increased TGF-beta signaling in diabetic retinal vessels, we plan to test the hypothesis that excess TGF-beta signaling contributes to the characteristic vascular pathology of diabetic retinopathy. The project is made especially exciting by the opportunity to use a new small molecule inhibitor of TGF-beta type I receptor kinase, named SM16, that is orally active, a most appealing feature for translational steps.
We aim to develop and validate in diabetic rats a drug strategy based on SM16 for non-invasive, long-term, and on-target prevention of the excess TGF-beta signaling in retinal vessels. The precise aim is to bring TGF-beta signaling back to control values without reducing basal TGF-beta activity. We will use the inhibitor to learn the molecular effects of excess TGF-beta signaling on diabetic retinal vessels. We will then test whether by taking away such effects, the retinal capillaries are protected from the cell death and remodeling that lead to their final demise in diabetes. In the same rats we will also examine the effects of SM16 on the development of the typical renal pathology. Finally, we will examine the TGF-beta pathway in human diabetic retinal vessels (postmortem eyes). A combination of positive results in the preclinical studies and the human diabetic retina will identify excess TGF-beta signaling as a contributor to the vascular pathology of diabetic retinopathy and will stimulate investigation and development of drugs to modulate safely TGF-beta activity in humans. In addition, the studies are poised to generate a paradigm for applications of anti-TGF-beta therapy to other pathologies.
The studies proposed address diabetic retinopathy, the most common and dreaded complication of diabetes. We seek to identify processes that are active at early stages of the development of retinopathy, so that we may develop the best drug strategy for prevention of the damage inflicted by diabetes to the retinal vessels. Such work has now uncovered a possible role in diabetic retinopathy of a multifunctional growth factor named TGF-beta. TGF-beta has been known to be involved in several vascular pathologies, but has never before been associated with diabetic retinopathy. This project intends to test whether reducing the increased TGF-beta caused by diabetes will protect the retinal vessels from damage and ultimately death. The project is exciting for three reasons. First, it will test a new inhibitor of TGF-beta that can be administered by mouth, and therefore would accelerate potential clinical application. Second, if the results show that returning to normal levels the excess TGF-beta activity caused by diabetes does in fact protect the retinal vessels, we will have a precise molecular target to be brought to test for the prevention of human diabetic retinopathy. Third, being TGF-beta implicated in multiple vascular pathologies --from kidney disease in diabetic and nondiabetic individuals, to vascular malformations in genetic syndromes, to abnormal vascular wall remodeling in hypertension and atherosclerosis--, the development of drug strategies to modulate the activity of TGF-beta will find interest and use in several fields of medicine.
|Dagher, Zeina; Gerhardinger, Chiara; Vaz, Joseph et al. (2017) The Increased Transforming Growth Factor-? Signaling Induced by Diabetes Protects Retinal Vessels. Am J Pathol 187:627-638|
|Zerbini, Gianpaolo; Maestroni, Anna; Palini, Alessio et al. (2012) Endothelial progenitor cells carrying monocyte markers are selectively abnormal in type 1 diabetic patients with early retinopathy. Diabetes 61:908-14|
|Gerhardinger, Chiara; Dagher, Zeina; Sebastiani, Paola et al. (2009) The transforming growth factor-beta pathway is a common target of drugs that prevent experimental diabetic retinopathy. Diabetes 58:1659-67|