Potential Therapeutic Roles for Inhibition of the PI3K/Akt/mTOR Pathway in the Pathophysiology of Diabetic Retinopathy

Abstract

Novel therapeutics such as inhibitors of PI3K/Akt/mTOR pathway presents a unique opportunity for the management of diabetic retinopathy (DR). Second generation mTOR inhibitors have the prospect to be efficacious in managing various stages of disease progression in DR. During early stages, the mTOR inhibitors suppress HIF-1α, VEGF, leakage, and breakdown of the blood-retinal barrier. These mTOR inhibitors impart a pronounced inhibitory effect on inflammation, an early component with diverse ramifications influencing the progression of DR. These inhibitors suppress IKK and NF-κB along with downstream inflammatory cytokines, chemokines, and adhesion molecules. In proliferative DR, mTOR inhibitors suppress several growth factors that play pivotal roles in the induction of pathological angiogenesis. Lead mTOR inhibitors in clinical trials for ocular indications present an attractive treatment option for chronic use in DR with favorable safety profile and sustained ocular pharmacokinetics following single dose. Thereby, reducing dosing frequency and risk associated with chronic drug administration.

Figure 1

Schematic of the PI3K/Akt/mTOR Pathway. pathway highlights downstream effectors pertinent to the development of diabetic retinopathy along with the benefit of dual inhibitors of mTOR (TORC1 and TORC2) that prevent feedback activation and prevent downstream effectors that are detrimental in the progression of diabetic retinopathy. References consulted for Figure 1: [56], Paloma Pharmaceuticals presentation files, and Angioceutics International.

Figure 2

Oxygen-induced retinopathy model-retinal flat mount. Seven-day old SV129 mouse pups were put at 70% oxygen for 5 days, removed to normal air, and injected intraperitoneal with Palomid 529 for 5 days. The animals were then sacrificed and the eyes removed and fixed in 10% formalin for 30 min. The retinas were isolated, blocked for 1 hr in PBS containing 1% BSA, 1% goat serum, and 0.5% TX-100, stained overnight with 10 μg/mL BS-1 lectin labeled with FITC (Sigma-Aldrich), washed in PBS and flat mounted.