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Physiopathology of ocular diseases:
Therapeutic innovations

Our team is dedicated to translational research in the field of ophthalmology, mostly but not solely in the field of retina. The questions are raised by clinical observational studies and from the analysis of effects of commonly used drugs (i.e. anti-VEGF and corticoids). Questions also emerge from risks of ocular exposure to environmental burdens (i.e. light exposure) in collaboration with National Agencies. Our priorities are driven by unmet needs and innovation. In addition to cellular and animal models, human biologic material is used to validate hypotheses.
To speed clinical translation and proof of concept in man, we favor the repositioning of know drugs in specific ocular formulation and/or new drug delivery systems. Research performed in the team is able to fill the gap between discovery and proof of concept in man. Valorization is considered for allowing further developments of the research conducted in the team.
General strategy: Our team’s objectives are to identify key regulatory molecular targets involved in the pathogenesis of macular oedema and retinal cell death, accessible to modulation by drugs, administered locally, and applicable to retinal diseases of various origins. To speed drug development process, repositioning of known molecules is favoured. Chorioretinopathy (CSCR) and diabetic retinopathy (DR) are taken as model diseases for first in man proof of concept.


Axis 1: Mechanisms of cell death and oedema in retinal multifactorial diseases

The team concentrates transversally on retinal pigment epithelium (RPE) and choroid complex, which importance is being increasingly recognized as optimized and novel imaging technologies allow its analysis. RPE/ choroid complex is the earliest site of damage in age-related macular degeneration (AMD), DR and CSCR.

We focus on the links between RPE dysfunction, including  transports and autopagy/phagocytosis, and cell death during aging and diseases.

 

Axis 2: Local delivery of anti edematous and neuroprotective drugs- pre clinical development.

We have previously validated several pathways involved in the pathogenesis of retinal edema and cell death, that can be regulated by known drugs repositionned and formulated for eye diseases. We are deciphering their downstream effectors, testing optimized formulations and performing pharmacokinetics/dynamics. For small molecules, topical micellar formulation and intraocular particulate polymeric sytems are developped. Different signaling pathways and molecules are currently studied.

 

Axis 3:  Human validation – clinical studies

First in amn, phase Ib/IIa studies.

 

Team Leader:  Françine BEHAR-COHEN (PU-PH; Univ Paris Descartes)

 

Team Members:

Researchers: Marc. ABITBOL (MCU-PH; Univ Paris Descartes), Claudine. BOTTERI (PU em; Univ Franche-Comté), Jean-Louis BOURGES (PU-PH; Univ Paris Descartes,) Elodie BOUSQUET (PHU; Univ Paris Descartes) , Dominique BREMOND-GIGNAC (PU-PH; Univ Paris Descartes), Antoine BREZIN (PU-PH; Univ Paris Descartes), Yves COURTOIS (DR em; Inserm), Remy DAILLEUX, (MCU-PH; Univ Paris Descartes), M. EL SANHARAWI (PHU; Univ Paris Descartes), , Elsa KERMORVANT (MCU-PH; Univ Paris Descartes), Patricia LASSIAZ (DR; CDD), Frédéric MASCARELLI (DR; Inserm), Alexandre MATET (CCA; AP-HP), Dominique MONNET (PU-PH; Univ Paris Descartes), Emilie PICARD (CR; Inserm), Pierre-Raphaël ROTHSCHILD (CCA; AP-HP), Alicia TORRIGLIA (DR; Inserm),  M. ZHAO-HU (CR; Inserm)

Technical staff: Marianne BERDUGO-POLAK (IE; Inserm),   Kimberley DELAUNAY (IE; CDD), Emmanuelle GELIZE-DUVIGNEAU (AI; Inserm),  Thara JAWORSKI (AI; CDD), Laurent JONET (Tec, Inserm), Claudia LUBIN (Adj Tec; Univ Paris Descartes), Marie-Christine NAUD (Tec; Inserm), Julia PARDO (Adj Tec; CDD).

Young Researchers: Jérémie CANONICA (Post-Doc) Elige CHBAT (PhD Student), Alejandra DARUICH-MATET (PhD Student), Jenny YOUALE-TEMBOU (PhD Student).

Students: Anais FRANCON (Master Student), Aurélie TIMSIT (Master Student), Daniela RODRIGUEZ-BRAZ (Master Student).

Administration: Thérèse BUCCINO-RANJIT (Adj Tec; Univ Paris Descartes)


 

Publications :

  • Mineralocorticoid receptor antagonism reduces choroidal neovascularization: Implication for wet AMD Zhao M, Mantel I, Gelize E,  Li X, Xie X, Arboleda A, Seminel M, Levy-Boukris R,  Dernigoghossian M,  Prunotto A, Andrieu-Soler C, Rivolta C,  Canonica J, Naud MC, Lechner S, Farman N, Bravo-Osuna I, Herrero-Vanrell R, Jaisser F, Behar-Cohen F. Nature Communication 2018, In press
  • Iron is neurotoxic in retinal detachment and transferrin confers neuroprotection 
    Daruich A, Le Rouzic Q, Jonet L, Naud MC, Kowalczuk L,  Pournaras JA,  Boatright JH, Thomas A, Turck N Moulin A, Behar-Cohen F*, Picard E. Science Advances 2018, In press
  • Towards an Optimized Use of Ocular Corticosteroids: EURETINA Award Lecture 2017.
    Behar-Cohen F. Ophthalmologica. 2018;240(2):111-119
  • AβPP-induced UPR Transcriptomic Signature of Glial Cells to Oxidative Stress as an Adaptive Mechanism to Preserve Cell Function and Survival. Chalour N, Maoui A, Rat P, Massicot F, Dutot M, Faussat AM, Devevre E, Limb A, Warnet JM, Treton J, Dinet V, Mascarelli F. Curr Alzheimer Res. 2018;15(7):643-654
  • Mechanisms of macular edema: Beyond the surface.Daruich A, Matet A, Moulin A, Kowalczuk L, Nicolas M, Sellam A, Rothschild PR, Omri S, Gélizé E, Jonet L, Delaunay K, De Kozak Y, Berdugo M, Zhao M, Crisanti P, Behar-Cohen F. Prog Retin Eye Res. 2018 Mar;63:20-68
  • Non-viral ocular gene therapy, pEYS606, for the treatment of non-infectious uveitis: Preclinical evaluation of the medicinal product. Touchard E, Benard R, Bigot K, Laffitte JD, Buggage R, Bordet T, Behar-Cohen F J Control Release. 2018 Sep 10;285:244-251.
  • Tolerance of high and low amounts of PLGA microspheres loaded with mineralocorticoid receptor antagonist in retinal target site. Zhao M, Rodríguez-Villagra E, Kowalczuk L, Le Normand M, Berdugo M, Levy-Boukris R, El Zaoui I, Kaufmann B, Gurny R, Bravo-Osuna I, Molina-Martínez IT, Herrero-Vanrell R, Behar-Cohen F.J Control Release. 2017 Nov 28;266:187-197.
  • The Academic-Industrial Complexity: Failure to Launch. Levin LA, Behar-Cohen F. Trends Pharmacol Sci. 2017 Dec;38(12):1052-1060
  • Effects of white light-emitting diode (LED) exposure on retinal pigment epithelium in vivo.
    Jaadane I, Villalpando Rodriguez GE, Boulenguez P, Chahory S, Carré S, Savoldelli M, Jonet L, Behar-Cohen F, Martinsons C, Torriglia A. J Cell Mol Med. 2017 Dec;21(12):3453-3466.
  • ROCK-1 mediates diabetes-induced retinal pigment epithelial and endothelial cell blebbing: Contribution to diabetic retinopathy. Rothschild PR, Salah S, Berdugo M, Gélizé E, Delaunay K, Naud MC, Klein C, Moulin A, Savoldelli M, Bergin C, Jeanny JC, Jonet L, Arsenijevic Y, Behar-Cohen F*, Crisanti P. Sci Rep. 2017 Aug 18;7(1):8834
  • Light-induced retinal damage using different light sources, protocols and rat strains reveals LED phototoxicity. Krigel A, Berdugo M, Picard E, Levy-Boukris R, Jaadane I, Jonet L, Dernigoghossian M, Andrieu-Soler C, Torriglia A, Behar-Cohen F. Neuroscience. 2016 Dec 17;339:296-307.
  • Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis.
    Daruich A, Matet A, Dirani A, Bousquet E, Zhao M, Farman N, Jaisser F, Behar-Cohen F.
    Prog Retin Eye Res. 2015 Sep;48:82-118.
  • Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Nguyen QD, Merrill PT, Jaffe GJ, Dick AD, Kurup SK, Sheppard J, Schlaen A, Pavesio C, Cimino L, Van Calster J, Camez AA, Kwatra NV, Song AP, Kron M, Tari S, Brézin AP.
    Lancet. 2016 Sep 17;388(10050):1183-92.
  • No market, go away! | Francine Behar-Cohen | TEDxC

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