RPIB - RECHERCHES PARTENARIALES ET INNOVATION BIOMEDICALE

Innovative protein therapies for retinal diseases – Innovision

Submission summary

Age Related Macular Degeneration (AMD) is the first cause of social blindness in the elderly population. Wet AMD resulting from the abnormal growth of neovessels originating from the choroids towards the retina, complicates about 40% of all AMD and choroidal neovascularization (CNV) induce 90% of severe vision loss. Dry AMD leads to progressive central vision loss due to retinal pigment epithelial cell (RPE), photoreceptor and choroids atrophy. Oxidative stress and inflammation in the ocular microenvironment are recognized as major risk factors for AMD. More particularly, complement factor H (CFH) polymorphism as a missense variant at position 402 of CFH, resulting in a Tyr-to-His (Y402H) exchange, increases the risk for AMD 4.6-fold in persons heterozygous for the haplotype and 7.4-fold in persons homozygous for it, identifying complement factor as a main potential therapeutic target. However, which activated fraction in the complement cascade should be inhibited, without impairing the natural debris clearance in the outer retina, remains controversial and the exact intrinsic role of CFH in the retina remains poorly understood. The other main target in wet AMD is VEGF, and anti VEGF strategies are currently used in the clinic with a major effect on leakage but not on CNV themselves. Moreover, anti VEGF therapies require monthly injection into the eye, which represents an important drawback of these treatments.
This project associates three French biotech companies (LFB Biotechnologies, SISENE and EYEVENSYS) and one academic team (UMRS 872; team 17: Physiopathology of ocular diseases: Therapeutic innovations) to develop therapeutic solutions for AMD by a sustained local delivery of two therapeutic proteins that both aim at restoring the inflammatory and angiogenic balance of the ocular micro-environment.
CFH will be produced by the LFB, France. Our preliminary data on the in vitro and in vivo effects of human plasma-purified CFH on retinal cells showed that active human CFH is not deleterious on human retinal cells in vitro, or in mouse retina after chronic intraperitoneal injections. Moreover, we demonstrate that CFH is able to mitigate retinal degeneration in a mouse model of photoreceptor degeneration. One aim of this project is to identify CFH variants with specific neuroprotective and/or anti-angiogenic properties on pertinent models of degenerative and angiogenic retinal disorders, as candidates for pre-clinical development.
SISENE is the exclusive licensee of Netrin-4. Originally identified as an axonal guidance molecule, Netrin-4 is a laminin-like secreted protein also involved in angiogenesis. Our preliminary results have shown that netrin-4 is produced in the eye in a murine CNV model and that local delivery of human-netrin-4 reduces CNV formation. One aim of this project is to identify Netrin-4 variants with specific enhanced anti-angiogenic and/or neuroprotective activities, as candidates for pre-clinical development.
The new variants of CFH and Netrin-4 could add intellectual property value to the project.
For a local and sustained delivery of the variants into the eye, electroporation will be used. EYEVENSYS, will optimize the already patented ciliary muscle electrotransfer technology that allows the intraocular secretion of therapeutic proteins produced the ciliary muscle cells after electroporation of the plasmids encoding the protein. For a more targeted delivery in RPE cells and in the choroid, a supra-choroidal transfection approach will be developed.
UMRS 872; team 17, already collaborating with LFB, SISENE and EYEVENSYS, will bring its expertise in retinal cell biology and animal models to allow for a validation of the CFH and Netrin-4 variants alone or in combination in relevant and validated models.
Innovision project brings a new integrated vision of innovative therapeutic proteins for the treatment of AMD.

Project coordination

Francine BEHAR-COHEN (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION REGIONALE PARIS 6) – francine.behar@gmail.com

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM DR Paris 6 INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION REGIONALE PARIS 6
SISENE SISENE
LFB Biotechnologies LFB BIOTECHNOLOGIES
Eyevensys Eyevensys

Help of the ANR 1,350,000 euros
Beginning and duration of the scientific project: December 2011 - 48 Months

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