Diabetic Retinopathy Reversed by Intravitreous Application of Retinol Binding Protein 3
Authors: YOKOMIZO HISASHI , PARK KYOUNGMIN , CLERMONT ALLEN , MAEDA YASUTAKA , FICKWEILER WARD , ISHIKADO ATSUSHI , LI QIAN , TINSLEY LIANE J. , POBER DAVID M. , WU I-HSIEN , AIELLO LLOYD P. , KEENAN HILLARY A. , SUN JENNIFER , KING GEORGE L. 
Published: June 2018

The Joslin Medalists study, enrolling people with type 1 diabetes of &gt;50 years, suggested protective factors exist against diabetic retinopathy (DR), even in the presence of hyperglycemia. Proteomic analysis of retina and vitreous suggested that Retinol Binding Protein 3 (RBP3), secreted by photoreceptors, to be elevated in the Medalists without vs. those with advanced DR. This finding was confirmed by ELISA RBP3 assays in replicating vitreous samples of Medalists and other diabetic patients. In contrast, vitreous VEGF levels increased with DR severity; resulting in decreasing RBP3/VEGF with worsening DR. Transgenic mice overexpressing RBP3 targeted to the photoreceptors prevented diabetes induced retinal capillary permeability and formation of acellular capillaries. To determine whether RBP3 can inhibit DR progression, recombinant human RBP3 (rhRBP3) was injected intravitreously (IVT) in rats with VEGF or after 2 months of diabetes. IVT injection of rhRBP3 inhibited VEGF induced increases in retinal vascular permeability both after a few min or 1 day post-VEGF injections (p=0.009 or p=0.01), respectively. After 2 months of diabetes, IVT rhRBP3 reversed capillary permeability to levels of nondiabetic rats (p=0.007), whereas boiled hRBP3 was ineffective. Surprisingly, IVT rhRBP3 also reduced retinal expression of VEGF and IL-6 in diabetic rats and normalized retinal function, as measured by B wave amplitude of electroretinography. Using cultured retinal endothelial cells and Muller cells, the addition of rhRBP3 inhibited VEGF- or high glucose-induced cell migration, possibly by binding to VEGF receptors. Surprisingly, rhRBP3 also inhibited high glucose-induced expression of VEGF and IL-6 mRNA levels (p=0.05) similar to in vivo studies. Thus, IVT application of RBP3 can intervene to delay, stop and reverse diabetes-induced neuro- and vascular-retinal functional and inflammatory abnormalities, strongly supporting a therapeutic potential for the use of RBP3 for DR.

Disclosure
H. Yokomizo: None. K. Park: None. A. Clermont: Consultant; Self; Kalvista Pharmaceuticals. Y. Maeda: None. W. Fickweiler: None. A. Ishikado: Employee; Self; Sunstar Inc.. Employee; Spouse/Partner; Sunstar Inc.. Q. Li: None. L.J. Tinsley: None. D.M. Pober: None. I. Wu: None. L.P. Aiello: Consultant; Self; Novo Nordisk Inc., Sanofi Genzyme. Stock/Shareholder; Self; Kalvista Pharmaceuticals, Inc.. Consultant; Self; Kalvista Pharmaceuticals, Inc. H.A. Keenan: Research Support; Self; Sanofi. Employee; Self; Sanofi Genzyme. J. Sun: Other Relationship; Self; Novartis Pharmaceuticals Corporation. Research Support; Self; Genentech, Inc., Optovue, Incorporated, Boston Micromachines Corporation, Adaptive Sensory Technology, Kalvista Pharmaceuticals, Inc.. Other Relationship; Self; Novo Nordisk Inc. G.L. King: Research Support; Self; Sanofi-Aventis.