Carboxyamidotriazole

We evaluated the safety and bioactivity of carboxyamidotriazole (CAI) using two approaches, a polymeric CAI-PLGA nanoemulsion in the mouse model of choroidal neovascularization (CNV) and CAI-loaded bioresorbable intravitreal implant in a rabbit model of vascular leakage.

Mice underwent laser rupture of Bruch's membrane to induce CNV followed by a single (2 µL volume) intravitreal injection of either vehicle (n = 11); CAI nanoparticles (0.5 µg, 1 µg, 2 µg, 400 nM, 800 nM, and 1.6 µM, respectively); aflibercept 10 µg; or CAI nanoparticles (1 µg) + aflibercept 10 µg. New Zealand white rabbits underwent either sham intravitreal injection, aflibercept 500 µg injection, or CAI-PLGA intravitreal implant. Vascular leakage was induced with injections of VEGF on days 23 and 53. On days 30 and 60, all groups underwent vitreous fluorophotometry and fundus imaging. On day 60, the rabbits were euthanized, and their eyes were enucleated.

Intravitreal injection of the CAI-Nano at the dose of 1 µg significantly decreased choroidal neovascular volume, to 25% of saline on day 7 and 30% on day 14, which was comparable to aflibercept. Vitreous fluorophotometry revealed significantly lower levels of fluorescein in the aflibercept and CAI implant groups compared to the sham group on day 30. On day 60, the CAI implant group showed significantly reduced neovascularization as compared with the aflibercept groups. No toxicity was observed in any group.

CAI in nanoparticle formulation or as a sustained release bioresorbable implant showed potent efficacy and caused no retinal toxicity in murine and rabbit models.

CAI demonstrates strong potential as a sustained release anti-angiogenic therapy with effective long-term durability.

Patients with non-proliferative macular telangiectasia type 2 (MacTel) have ganglion cell layer (GCL) and nerve fibre layer (NFL) loss, but it is unclear whether the thinning is progressive. We quantified the change in retinal layer thickness over time in MacTel with and without diabetes.

In this retrospective, multicentre, comparative case series, subjects with MacTel with at least two optical coherence tomographic (OCT) scans separated by >9 months OCTs were segmented using the Iowa Reference Algorithms. Mean NFL and GCL thickness was computed across the total area of the early treatment diabetic retinopathy study grid and for the inner temporal region to determine the rate of thinning over time. Mixed effects models were fit to each layer and region to determine retinal thinning for each sublayer over time.

115 patients with MacTel were included; 57 patients (50%) had diabetes and 21 (18%) had a history of carbonic anhydrase inhibitor (CAI) treatment. MacTel patients with and without diabetes had similar rates of thinning. In patients without diabetes and untreated with CAIs, the temporal parafoveal NFL thinned at a rate of −0.25±0.09 µm/year (95% CI [−0.42 to –0.09]; p=0.003). The GCL in subfield 4 thinned faster in the eyes treated with CAI (−1.23±0.21 µm/year; 95% CI [−1.64 to –0.82]) than in untreated eyes (−0.19±0.16; 95% CI [−0.50, 0.11]; p<0.001), an effect also seen for the inner nuclear layer. Progressive outer retinal thinning was observed.

Patients with MacTel sustain progressive inner retinal neurodegeneration similar to those with diabetes without diabetic retinopathy. Further research is needed to understand the consequences of retinal thinning in MacTel.