Amadorins as a Novel Oral Therapeutic for Diabetic Retinopathy

Praetego, Inc., Durham NC

Investigators

Abstract

PROJECT SUMMARY Diabetic Retinopathy (DR) is a serious diabetic complication that is the leading cause of vision loss in working- age adults, affecting more than 7.5 million people in the USA. It causes more new cases of blindness than any other eye disease in people between the ages of 18 and 65. The anti-VEGF treatments can slow the progress of DR in many patients but are only used after significant vascular lesions have already developed. These intraocular antibody injections are expensive, painful, inconvenient for patients and introduce a risk of developing endophthalmitis. The successful development of an orally administered small molecule therapeutic that protects the retina at an earlier stage of the disease would represent a significant breakthrough in the clinical management of this diabetic complication. Praetego Inc. plans to address DR by developing a novel oral medication that may protect the retina from the damage of hyperglycemia at the earliest stages of the disease. Hyperglycemia is the key common factor linking all diabetic complications. Direct reaction of proteins with glucose leads to formation of so-called advanced glycation end products (AGEs), a process accompanied and accelerated by production of damaging dicarbonyls such as methylglyoxal, reactive oxygen species and free radicals. There is much evidence implicating AGE formation as a causative factor in all microvascular complications of diabetes. Our project advances our novel and potent AGE inhibitor, PTG-630, for treating DR, which is demonstrating neuroprotection in preclinical studies on diabetic peripheral neuropathy (DPN). It avidly binds redox metal ions, especially Cu2+, which endows it with the additional capacity to be a general antioxidant. PTG-630 has been well characterized in safety pharmacology and ADME (absorption, distribution, metabolism, excretion), and physical-chemical properties. This dual-acting small molecule has excellent penetration into the brain and CSF after oral administration due to its excellent cellular permeability. In preliminary pharmacokinetic studies, we have confirmed that it quickly reaches the retina, an organ where there is evidence of neurovascular damage preceding vascular lesions in DR. Thus, in this Phase I proposal, we will test the hypothesis that: orally administered PTG-630 can prevent retinal neurodegeneration, vision loss and retinal inflammation in STZ- diabetic rats. Our Specific Aims are: 1) determine the effectiveness of PTG-630 (in its tri-HCl salt form) to prevent vision loss and diabetes-induced retinal disease in the streptozotocin (STZ)-diabetes model using female Long- Evans rats; and 2) do the same in male Long-Evans rats. We will accomplish this by a) measuring visual function through behavioral optokinetic analysis, using spatial frequency threshold and contrast sensitivity; b) measuring inner and outer retinal thickness using spectral domain optical coherence tomography (SD-OCT); and c) measuring AGE accumulation, macro-glial reactivity, and retinal ganglion cell survival. Successful completion of this project will provide data supporting more thorough studies by a planned Phase II STTR submission while helping prepare for IND-enabling studies following an early pre-IND FDA meeting.