Abstract
Purpose :
ARA290 (cibinetide), a novel peptide based on the Helix-B domain of erythropoietin, is anti-inflammatory and tissue-protective, and has previously been shown to reduce retinal vascular leakage and capillary dropout in diabetic rodent retina. We sought to assess the tissue protective capabilities of ARA290 in the neural retina during diabetes, by determining the potential of ARA290 to protect against structural and functional neural retinal dysfunction. Additionally, the effect of ARA290 treatment on retinal immune cell activation and retinal cytokine expression was assessed.
Methods :
Diabetes was induced in C57BL/6J mice by streptozotocin injection, and animals assigned into treatment groups receiving intraperitoneal injection of; vehicle, 30, or 60µg/kg ARA290 for 12 weeks. Retinal structure and function was assessed by optical coherence tomography, and scotopic electroretinography respectively. Gene expression of pro- and anti-inflammatory cytokines was assessed in retinal tissue alongside immune cell activation.
Results :
Diabetic HbA1c levels across treatment groups were significantly elevated vs non-diabetic controls (p<0.0001; One-Way ANOVA), and ARA290 treatment had no effect on haematocrit. At higher light levels, photoreceptor a-wave amplitude was significantly decreased in vehicle-treated diabetic mice compared to non-diabetic controls (p<0.01; two-way ANOVA, Bonferroni). ARA290 treatment (60µg/kg) attenuated this decrease in rod a-wave amplitude. Similarly, a decrease in ON bipolar cell function (b wave amplitude) observed in vehicle-treated diabetic mice compared to non-diabetics, was significantly attenuated in the 60µg/kg ARA290-treated diabetic mice (p<0.0001; two way ANOVA). ARA290 treatment ameliorated retinal thinning observed in the vehicle-treated diabetic animals after 12 weeks of diabetes, with retinal thickness approaching non-diabetic control levels. Increased pro-inflammatory TNFα, IL-1β, and ICAM-1 retinal mRNA levels under diabetic conditions were partially attenuated with ARA290 treatment.
Conclusions :
ARA290 confers neuroprotective effects on diabetic rodent retina, through reducing retinal thinning and pro-inflammatory stimuli, whilst preserving neural retinal function. The neuroprotective capability of ARA290 may have therapeutic potential for patients with diabetic retinopathy.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.