Direct Tie2 Agonists Stabilize Vasculature for the Treatment of Diabetic Macular Edema.

Purpose: Diabetic macular edema (DME) is the leading cause of vision loss and blindness among working-age adults. Although current intravitreal anti-vascular endothelial growth factor (VEGF) therapies improve vision for many patients with DME, approximately half do not achieve the visual acuity required to drive. We therefore sought additional approaches to resolve edema and improve vision for these patients. Methods: We explored direct agonists of Tie2, a receptor known to stabilize vasculature and prevent leakage. We identified a multivalent PEG-Fab conjugate, Tie2.1-hexamer, that oligomerizes Tie2 and drives receptor activation and characterized its activities in vitro and in vivo. Results: Tie2.1-hexamer normalized and stabilized intercellular junctions of stressed endothelial cell monolayers in vitro, suppressed vascular leak in mice under conditions where anti-VEGF alone was ineffective, and demonstrated extended ocular exposure and robust pharmacodynamic responses in non-human primates. Conclusions: Tie2.1-hexamer directly activates the Tie2 pathway, reduces vascular leak, and is persistent within the vitreal humor. Translational Relevance: Our study presents a promising potential therapeutic for the treatment of DME.

Comparison of two ultrashort echo time sequences for the quantification of T1 within phantom and human Achilles tendon at 3 T.

Ultrashort echo time (UTE) techniques enable direct imaging of musculoskeletal tissues with short T2 allowing measurement of T1 relaxation times. This article presents comparison of optimized 3D variable flip angle UTE (VFA-UTE) and 2D saturation recovery UTE (SR-UTE) sequences to quantify T1 in agar phantoms and human Achilles tendon. Achilles tendon T1 values for asymptomatic volunteers were compared to Achilles tendon T1 values calculated from patients with clinical diagnoses of spondyloarthritis (SpA) and Achilles tendinopathy using an optimized VFA-UTE sequence. T1 values from phantom data for VFA- and SR-UTE compare well against calculated T1 values from an assumed gold standard inversion recovery spin echo sequence. Mean T1 values in asymptomatic Achilles tendon were found to be 725±42 ms and 698±54 ms for SR- and VFA-UTE, respectively. The patient group mean T1 value for Achilles tendon was found to be 957±173 ms (P<0.05) using an optimized VFA-UTE sequence with pulse repetition time of 6 ms and flip angles 4, 19, and 24°, taking a total 9 min acquisition time. The VFA-UTE technique appears clinically feasible for quantifying T1 in Achilles tendon. T1 measurements offer potential for detecting changes in Achilles tendon due to SpA without need for intravenous contrast agents.