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From physiopathology of retinal diseases towards clinical developments

Retinal diseases are the major causes of blindness in industrialized countries with an increasing burden due to population aging and to the increase of the incidence of diabetes mellitus. Para-inflammation contributes to retinal homeostasis during aging and in the diabetic retina, but genetic, epigenetic, environmental factors (oxidative stress, smoking, light exposure, nutrition…) can unbalance this adaptive response towards pathogenic infra-clinical inflammatory processes. Amongst inflammatory consequences of this inbalance we found, for instance, macular edema (ME), a clinical sign with poorly understood mechanisms. Pathological vascular remodeling and fibrosis, are the major causes of vision loss.

 

 

Figure 1: macular edema (ME) on histology and optical coherence tomography (OCT). This changes result in central blurred vision

 

 

 

 

 

 

The immunosuppressive micro-environment, the anti-oxydant mechanisms and the hydro-ionic drainage that maintain the retina in a dehydrated and transparent state, are studied in normal retina. The deregulations of these mechanisms are analyzed in animal models of inflammation, retinal degeneration, and diabetic retinopathy as well as in patients. We use specific clinical diseases with pure phenotypes such as central serous chorioretinopathy, macular telangiectasia, toxic retinopathy, hereditary exudative vitreoretinopathy as disease models.

Our general strategy is summarized below:


 

Several axes are explored:


1. Transferrin and CFH: two endogenous anti-oxydant molecules

  Fréderic Mascarelli and Virginie Dinet work on the molecular mechanisms of action of the Complement inhibitor Factor H (CFH), strongly associated with the risk for developing AMD. This function is different from its already known role as a negative regulator of the complement activation through its alternative pathway. Appropriate ocular delivery of CFH is developed as a therapeutic strategy.


 Emilie Picard is involved in characterizing another important protein, associated with AMD, the transferrin, one the major regulator of iron metabolism in the retina. Protective strategies are being developed.

 

 

  2. Mechanisms of retinal cell death in response to oxidative or metabolic stress.


Alicia Torriglia and Slavica Krantic identifient les mécanismes de mort cellulaire non “classiques” impliqués dans les maladies rétiniennes et sur des cibles de régulation. Des corrélations  entre cerveau et rétine sont réalisées sur des modèles d’ataxie et de maladie d’Alzheimer. 

 

  3. Mechanisms of macular edema (ME):  Specific molecular organization of the macula, role of ocular barriers, hydro ionic balance control in the retina.

Patricia Lassiaz, Boubaker Omri, Marianne Berdugo-Polak and Y de Kozak work on the molecular characterization of the macula and the identification of regulators of the retinal barriers in normal and  diabetic conditions.
Min Zhao and Francine Behar-Cohen analyse the mechanisms of action of corticosteroids on the normal and the pathological retina, particularly the role of the mineralocorticoids pathways in the diabetic retina. This work is made in collaboration with team 1 of the CRC.

  

 Marc Abitbol will explore the involvement of the cholinesterase pathway in the neurovascular junction in the retina.

 

 

 

 4.Mechanisms of fibro-glial proliferation in the retina: Genetic identification of familial vitreoretinopathy, molecular and functional analysis and  involvement of the identified pathways in other more common diseases.

Sophie Valleix is responsible for this development.

 


 5. Mechanisms of action of known anti-edematous drugs  


Charlotte Andrieu-Soler and Francine Behar-Cohen are involved in understanding the molecular meachanisms of action of setroids and anti-VEGF in the retina and identify novel regulatory targets for the treatment of ME up to clinical proofs of concept.

 

6. Development of targeted drug delivery systems for the treatment of retinal diseases.

Francine Behar-Cohen Yvan Arsenijevic’s group develop gene delivery systems and evaluate new routes of ocular administration.


 

 

This is a multidisciplinary and translational project: Questions emerge from clinical observations, are answered by basic research, then validated on human samples and, when possible, through clinical trials.

 

 

 

 

Example of translational research from proposed mechanisms of action towards clinical application

Central serous chorioretinopathy affect 1/10 000 individuals and is the 4th cause of vision loss in the young population.  No treatment is currently validated. We have shown that mineralocorticoid receptors are efficient for treating this condition. This work was done in collaboration with team 1 (F. Jaisser)

 Team Leader: Francine BEHAR-COHEN (Pr)

Team Members: Marc ABITBOL (Dr), Claudine BOTTERI (Dr), Omri BOUBAKER (Dr), Jean-Louis BOURGES (Dr), Yves COURTOIS (Dr), Virginie DINET (Dr), Elsa KERMORVANT (Dr), Slavica KRANTIC (Dr), Patricia LASSIAZ (Dr), Frédéric MASCARELLI (Dr), Pierre-Raphael ROTHSCHILD (Dr), Alicia TORRIGLIA (Dr), Min ZHAO-HU (Dr).

Marianne BERDUGO-POLAK (Eng), Kimberley DELAUNAY (Eng), Emmanuelle GELIZE-DUVIGNEAU (Eng), Imène JAADANE (Eng), Laurent JONET (Tec), Quentin LE ROUZIC (Eng), Claudia LUBIN (Tec), Marie-Christine NAUD (Tec), Julia PARDO (Tec).

Céline BORRAS (PhD), Imène JAADANE (Post-Doc), Emilie PICARD (Post-Doc).

Administration: Thérèse BUCCINO-RANJIT

Contact details : 33 1 44 27 81 64   Email: therese.buccinoranjit@crc.jussieu.fr

 


Main Publications

  • Yu W, Bonnet M, Farso M, Ma K, Chabot JG, Martin E, Torriglia A, Guan Z, McLaurin J, Quirion R, Krantic S. The expression of apoptosis inducing factor (AIF) is associated with aging-related cell death in the cortex but not in the hippocampus in the TgCRND8 mouse model of Alzheimer's disease. BMC Neurosci. 2014 Jun 10;15:73.
  • Krantic S, Torriglia A. Retina: source of the earliest biomarkers for Alzheimer's disease? J Alzheimers Dis. 2014;40(2):237-43.
  • Omri S, Behar-Cohen F, Rothschild PR, Gélizé E, Jonet L, Jeanny JC, Omri B, Crisanti P. PKC mediates breakdown of outer blood-retinal barriers in diabetic retinopathy. PLoS One. 2013 Nov 29;8(11):e81600.
  • Bousquet E, Beydoun T, Zhao M, Hassan L, Offret O, Behar-Cohen F. Mineralocorticoid receptor antagonism in the treatment of chronic central serous chorioretinopathy: a pilot study. Retina. 2013 Nov-Dec;33(10):2096-102
  • El Sanharawi M, Touchard E, Benard R, Bigey P, Escriou V, Mehanna C, Naud MC, Berdugo M, Jeanny JC, Behar-Cohen F.Long-term efficacy of ciliary muscle gene transfer of three sFlt-1 variants in a rat model of laser-induced choroidal neovascularization. Gene Ther. 2013 Nov;20(11):1093-103.
  • Dinet V, Bruban J, Chalour N, Maoui A, An N, Jonet L, Buret A, Behar-Cohen F, Klein C, Tréton J, Mascarelli F.Distinct effects of inflammation on gliosis, osmohomeostasis and vascular integrity during amyloid beta-induced retinal degeneration. Aging Cell. Aging Cell. 2012 Aug;11(4):683-93.
  • Bruban J, Dinet V, Mascarelli F. The role of amyloid-β in retinal degeneration.c Adv Exp Med Biol. 2012;723:67-74.
  • Padron-Barthe, L., C. Lepretre, E. Martin, M. F. Counis, and A. Torriglia. Conformational modification of serpins transforms leukocyte elastase inhibitor into an endonuclease involved in apoptosis. Mol Cell Biol 2012; 27:4028-36.
  • Latour G, Kowalczuk L, Savoldelli M, Bourges JL, Plamann K, Behar-Cohen F, Schanne-Klein MC. Hyperglycemia-induced abnormalities in rat and human corneas: the potential of second harmonic generation microscopy. PLoS One. 2012;7(11):e48388.
  • Zhao M, Célérier I, Bousquet E, Jeanny JC, Jonet L, Savoldelli M, Offret O, Curan A, Farman N, Jaisser F, Behar-Cohen F.  Mineralocorticoid receptor involvement in rat and human ocular chorioretinopathy. J Clin Invest 2012 Jul 2;122(7):2672-9.
  • Valleix S, Gillmore JD, Bridoux F et al. Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin.  N Engl J Med. 2012 Jun 14;366(24):2276-83
  • Zhao M, Bousquet E, Valamanesh F, Farman N, Jeanny JC, Jaisser F, Behar-Cohen F. Differential regulations of AQP4 and Kir4.1 by triamcinolone acetonide and dexamethasone in the healthy and inflamed retina. Invest Ophthalmol Vis Sci. 2011 Aug 11;52(9):6340-7.
  • Touchard, E., M. Berdugo, P. Bigey, M. El Sanharawi, M. Savoldelli, M. C. Naud, J. C. Jeanny, and F. Behar-Cohen. Suprachoroidal Electrotransfer: A Nonviral Gene Delivery Method to Transfect the Choroid and the Retina Without Detaching the Retina. Mol Ther. 2012; Jan 17. 2011.304
  • El Sanharawi M, Kowalczuk L, Touchard E, Omri S, de Kozak Y, Behar-Cohen F. Protein delivery for retinal diseases: from basic considerations to clinical applications. Prog Retin Eye Res. 2010;29(6):443-65.
  • Kowalczuk, L., E. Touchard, S. Omri, L. Jonet, C. Klein, F. Valamanes, M. Berdugo, P. Bigey, P. Massin, J. C. Jeanny, and F. Behar-Cohen. Placental growth factor contributes to micro-vascular abnormalization and blood-retinal barrier breakdown in diabetic retinopathy. PLoS One 2011; 6:e17462.
  • Touchard, E., P. Heiduschka, M. Berdugo, L. Kowalczuk, P. Bigey, S. Chahory, C. Gandolphe, J. C. Jeanny, and F. Behar-Cohen. Non-viral gene therapy for GDNF production in RCS rat: the crucial role of the plasmid dose. Gene Ther. 2011, Oct 13. doi: 10.1038/gt.2011.154

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