José-Alain Sahel, MD

Retinal disease treatments including Rod-derived-Cone-Viability-Factor, translation/research on molecular and genetic factors in retinal disease progression and treatment/regenerative therapeutic treatments for retinal disease/research on retinal cell types for optogenetic treatments.

José-Alain Sahel is a clinician-scientist conducting research on vision restoration focusing on cellular and molecular mechanisms underlying retinal degeneration, and development of treatments for currently untreatable retinal diseases. José-Alain Sahel’s work has contributed to understanding and preventing vision loss from photoreceptor cell degeneration and developing several novel vision restoration strategies. His clinical research is closely entangled with experimental research (information processing, genetic therapeutic research including modeling), evidence of pre-clinical concepts, technological developments in imaging and surgery, and forming integrated site research on diseases of vision. He has conducted dozens of clinical trials on retinal conditions and led several first-in-human vision restoration clinical trials in gene therapy, retinal prosthesis and optogenetics.

Research Interests

1. Together with my team, I worked on the conception, development, and evaluation of innovative treatments for retinal diseases -with a special focus on genetic rod-cone dystrophies- including neuroprotection, stem cells, gene therapy, pharmacology, and artificial retina. I was the first to hypothesize and demonstrate that rod photoreceptors produce a protein that rescues cone photoreceptors, thereby maintaining light-adapted and high-resolution vision. We (with S. Mohand-Said and Thierry Leveillard) identified the underlying signal: Rod-derived Cone Viability Factor (RdCVF) and determined its mechanisms of action (stimulation of aerobic glycolysis, and antioxidant).
a. Mohand-Said S, Deudon-Combe A, Hicks D, Simonutti M, Forster V, Fintz AC, Léveillard T, Dreyfus H, Sahel JA. Normal retina releases a diffusible factor stimulating cone survival in the retinal degeneration mouse. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8357-62
b. Mohand-Saïd S, Hicks D, Léveillard T, Picaud S, Porto F, Sahel JA. Rod-cone interactions: development and clinical significance. Prog Retin Eye Res 2001; 20: 451-67.
c. Léveillard T, Mohand-Saïd S, Lorentz O, Hicks D, Fintz AC, Clérin E, Simonutti M, Forster V, Cavusoglu N, Chalmel F, Dollé P, Poch O, Lambrou G, Sahel JA. Identification and characterization of rod-derived cone viability factor. Nat Genet. 2004 Jul;36(7):755-9.
d. Aït-Ali N, Fridlich R, Millet-Puel G, Clérin E, Delalande F, Jaillard C, Blond F, Perrocheau L, Reichman S, Byrne LC, Olivier-Bandini A, Bellalou J, Moyse E, Bouillaud F, Nicol X, Dalkara D, van Dorsselaer A, Sahel JA, Léveillard T. Rod-derived Cone Viability Factor acts by stimulating aerobic glycolysis. Cell, 2015 May 7;161(4):817-32.

2. RdCVF use is now in translation as a possible therapeutic agent to save cones and treat a spectrum of retinal degenerative diseases as a mutation independent strategy.
a. Yang Y, Mohand-Said S, Danan A, Simonutti M, Fontaine V, Clerin E, Picaud S, Léveillard T, Sahel JA. Functional cone rescue by RdCVF protein in a dominant model of retinitis pigmentosa. Mol Ther. 2009 May;17(5):787-95.
b. Léveillard T, Sahel JA. Rod-derived cone viability factor for treating blinding diseases: from clinic to redox signaling. Science Translational Medicine. 2010 Apr 7;2(26):26ps16.
c. Byrne LC, Dalkara D, Luna G, Fisher SK, Clérin E, Sahel JA, Léveillard T, Flannery JG. Viral-mediated RdCVF and RdCVFL expression protects cone and rod photoreceptors in retinal degeneration. J Clin Invest. 2015;125(1):105-16.
d .Sahel JA, Bennett J, Roska B. Depicting brighter possibilities for treating blindness. Sci Transl Med. 2019 May 29;11(494). pii: eaax2324. The IND for the clinical trial has been granted in 2022.

3. Utilizing a variety of molecular and functional genomics approaches, my group aims to identify novel disease causing genes for retinal degenerations. Besides research on developmental biology, functional genomics, physiology and therapeutics, my team (with M.Paques, S. Mohand-Said and I. Audo) conducts research on genotype-phenotype correlations with high resolution in vivo non-invasive high-resolution retinal imaging techniques (optical coherence tomography and adaptive optics) aiming at identifying patients eligible for clinical application of innovative therapies. Together with M. Fink (Institut Langevin), I led a very competitive, large, ERC-Synergy grant (2014-2021) aiming at developing novel technologies for morpho-functional imaging of the visual system.
a.Roska B, Sahel JA. Restoring vision. Nature. 2018 May;557(7705):359-367
b.Blaize K, Arcizet F, Gesnik M, Ahnine H, Ferrari U, Deffieux T, Pouget P, Chavane F, Fink M, Sahel JA, Tanter M, Picaud S Functional ultrasound imaging of deep visual cortex in awake nonhuman primates. Proc Natl Acad Sci U S A. 2020 Jun 23;117(25):14453-14463
c.Sahel JA, Grieve K, Pagot C, Authié C, Mohand-Said S, Paques M, Audo I, Becker K, Chaumet-Riffaud AE, Azoulay L, Gutman E, Léveillard T, Zeitz C, Picaud S, Dalkara D, Marazova K. Assessing photoreceptor status in retinal dystrophies: from high resolution imaging to functional vision. Am J Ophthalmol. 2021 : S0002-9394(21)00212-9
d.Verschueren A., Boucherit L., Ferrari U., Fouquet S., Nouvel-Jaillard C., Paques M., Picaud S., Sahel JA. Planar polarity in primate cone photoreceptors: a potential role in Stiles Crawford effect phototropism, Commun Biol 5, 89 (2022)

4. We’ve developed a number of regenerative therapeutic approaches to restore vision such as gene therapy (including the first advanced trials on mitochondrial diseases) leading to the first demonstration in several large scale randomized trials of the efficacy of Gene Therapy in Leber Hereditary Optic Neuropathy.
a. Vignal C, Uretsky S, Fitoussi S, Galy A, Blouin L, Girmens JF, Bidot S, Thomasson N, Bouquet C, Valero S, Meunier S, Combal JP, Gilly B, Katz B, Sahel JA. Safety of rAAV2/2-ND4 Gene Therapy for Leber Hereditary Optic Neuropathy. Ophthalmology. 2018 Jun;125(6):945-947.
b. Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Biousse V, Vignal-Clermont C, Sergott RC, Klopstock T, Sadun AA, Barboni P, DeBusk AA, Girmens JF, Rudolph G, Karanjia R, Taiel M, Blouin L, Smits G, Katz B, Sahel JA. Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset. LHON Study Group. Ophthalmology. 2021 May;128(5):649-660.
c. Yu-Wai-Man P, Newman NJ, Carelli V, Moster ML, Biousse V, Sadun AA, Klopstock T, Vignal-Clermont C, Sergott RC, Rudolph G, La Morgia C, Karanjia R, Taiel M, Blouin L, Burguière P, Smits G, Chevalier C, Masonson H, Salermo Y, Katz B, Picaud S, Calkins DJ, Sahel JA. Bilateral Visual Improvement with Unilateral Gene Therapy Injection for Leber Hereditary Optic Neuropathy. Science Translational Medicine Dec 9; 12 (573) 2021: eaaz7423.
d. Nancy J Newman, Patrick Yu-Wai-Man, Prem S Subramanian, Mark L Moster, An-Guor Wang, Sean P Donahue, Bart P Leroy, Valerio Carelli, Valerie Biousse, Catherine Vignal-Clermont, Robert C Sergott, Alfredo A Sadun, Gema Rebolleda Fernández, Bart K Chwalisz, Rudrani Banik, Fabienne Bazin, Michel Roux, Eric D Cox, Magali Taiel, José-Alain Sahel, the LHON REFLECT Study Group, Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy, Brain, 2022;, awac421, https://doi.org/10.1093/brain/awac421

5. With B. Roska at the Institute of Ophthalmology of Basel, S.Picaud and Deniz Dalkara at Institut de la Vision in Paris, we demonstrated that different retinal cell types such as "dormant cones" and Ganglion Cells can be converted into “artificial photoreceptors” by targeting the expression of genetically encoded light sensors enabling mice with retinal degeneration to perform visually guided behaviors. I led the first demonstration of the efficacy of Optogenetics in partial function restoration in humans. I also led (with Dr. Palanker) the first in-human wireless artificial retina trial.
a. Busskamp V, Duebel J, Balya D, Fradot M, Viney TJ, Siegert S, Groner AC, Cabuy E, Forster V, Seeliger M, Biel M, Humphries P, Paques M, Mohand-Said S, Trono D, Deisseroth K, Sahel JA, Picaud S, Roska B. Genetic Reactivation of Cone Photoreceptors Restores Visual Responses in Retinitis pigmentosa. Science. 2010 329(5990):413-7.
b. Palanker D, Le Mer Y, Mohand-Said S, Muqit M, Sahel JA. Photovoltaic Restoration of Central Vision in Atrophic Age-Related Macular Degeneration. Ophthalmology. 2020 Feb 25: S0161-6420(20)30189-5.
c. Sahel JA, Boulanger-Scemama E, Pagot C, Arleo A, Galuppi F, Martel JN, Degli Esposti S, Delaux A, de Saint Aubert JB, de Montleau C, Gutman E, Audo I, Duebel J, Picaud S, Dalkara D, Blouin L, Taiel M, Roska B. Partial recovery of visual function in a blind patient after optogenetic therapy. Nature Medicine 2021 Jul;27(7):1223-1229.
d. Palanker D, Le Mer Y, Mohand-Said S, Sahel JA. Simultaneous Perception of Prosthetic and Natural Vision in AMD Patients, Nature Communications, (2022) 13:513

Publications