Purchase this article with an account.
Najate Aït-Ali, François Delalande, Alain Van Dorsselaer, Thierry D. Leveillard; Expression of RdCVF and RdCVL in non human primate retina: A credible animal model for the development of a clinical trial. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3066.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The bifunctional gene NXNL1 encodes two proteins by an alternative splicing, RdCVF that is secreted by rods and protects cones and the enzyme RdCVFL. The mode of action and the signalization of RdCVF and RdCVFL have been identified and integrated into a model system. RdCVF stimulates the renewal of cones outer segments and RdCVFL protects the cones against oxidative damages. A preclinical proof of concept based on a metabolic and redox treatment of retinitis pigmentosa (RP) is now ongoing. The translational research strategy is based on improving the technology, adapting clinical endpoints and on identification of biomarkers in animal models to conduct a clinical development. Prior to the launch the therapeutic innovation process of testing this new hopefulness treatment of RP, it is judicious to explore this signaling in a non human primate model. Our goal is to determine if the macaque is an appropriate model making the link between pre-clinical and clinical development. If in the macaque retina as in the mouse retina, RdCVF is only expresses in rods whereas RdCVFL is expresses in rods and cones, this model would be used for measuring the optimal dose to be used in human.
Macaque retina were dissected based on the Burke protocol. After isolated the fovea, the macula, the near, the mid and the far peripheral retina, RdCVF and RdCVFL expression were detected and compared by RT-PCR. A quarter of another macaque retina was lyses and the proteins RdCVF and RdCVFL were identified by mass spectrometry (MS/MS).
The macaque expresses the both messengers of NXNL1 gene but the RdCVF messenger is mostly express in near-mid and far retina whereas RdCVFL is express in both part of the retina, the center and the peripheral. In the whole retina macaque dissected which weighs 220 mg, seven peptides was identified with 62% protein sequence coverage with 4 that are common to both RdCVF and RdCVFL and 3 specific to RdCVFL.
As it was expected on the distribution of rods and cones on the retina, the fovea-macula part is mainly composed by cone photoreceptors whereas the more we get away from the retina, the more we essentially found rod photoreceptors. Like in the mouse model, RdCVF is only express by rods and could maintain cones alive. The macaque is a relevant model for this RdCVF/RdCVFL gene therapy strategy.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
This PDF is available to Subscribers Only