Genetics and therapy of retinal blindness and optic neuropathies

Christian HAMEL

 INM - U 1051

 80, rue Augustin Fliche, 34091 Montpellier

Phone: +33 4 99 63 60 10

Email: christian.hamel@inserm.fr

Website

The overall project of the team is to decipher the causes and pathophysiology of inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) and to design therapeutic strategies to prevent the degenerative processes. The team comprises several research groups on genetics, pathophysiology and therapy of retinal diseases, gene therapy, optic neuropathies. The activities of these groups are distributed into four research axes:

1. Human genetic studies using gene mapping and NGS sequencing, for gene discovery (recently RCBTB1, RTN4IP1, MAPKAPK3, CALHM3) and clinical/molecular diagnosis in the hospital clinical department (Gaël Manès, Béatrice Bocquet, Isabelle Meunier, Agathe Roubertie, Cécile Delettre, Guy Lenaers).

2. Inherited ION and IRD pathophysiology using animal models, patient skin fibroblasts and retinal cell cultures (retinal pigment epithelium, retinal ganglion cells). The mitochondrial metabolism is explored in dominant optic atrophy (DOA) OPA1 and Wolfram disease (WS) and the retinoid metabolism is analyzed in pigmentary retinopathies (RPE65, FATP1) (Agnès Muller, Emmanuelle Sarzi, Cécile Delettre, Philippe Brabet, Laurent Guillou).

3. Gene therapy and pharmacological treatment are tested using iPS for pigmentary retinopathies (choroideremia, retinitis punctata albescens) and animal models in DOA and WS. New gene therapy vectors for Stargardt disease and inhibitory peptides for visual cycle dysfunction are developed. A gene therapy biotech (Horama) is created for clinical trials (Vasiliki Kalatzis, Marie Péquignot, Philippe Brabet, Cécile Delettre).

4. With the help of the National Center for genetic sensory diseases in the hospital, we are undergoing clinical studies to understand the origins of certain macular dystrophies (Isabelle Meunier), choroideremia (Christian Hamel), retinitis punctate albescens (Christian Hamel), Wolfram syndrome (Agathe Roubertie) and others.

Keywords: retinal degeneration, optic atrophy, gene therapy, induced pluripotent stem cells, human genetics

Main publications

• Meunier* I, Lenaers* G, Bocquet B, Baudoin C, Piro-Megy C, Cubizolle A, Quilès M, Jean-Charles A, Cohen SY, Merle H, Gaudric A, Labesse G, Manes G, Péquignot M, Cazevieille C, Dhaenens CM, Fichard A, Ronkina N, Arthur SJ, Gaestel M, Hamel CP (2016). A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium. Hum Mol Genet 25:916-926.
• Angebault C, Charif M, Guegen N, Piro-Mégy C, Mousson de Camaret B, Procaccio V, Guichet P-O, Hebrard M, Manes G, Lebourcq N, Rivier F, Hamel CP, Lenaers G, Roubertie A (2015). Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability. Hum Mol Genet 24:3948-3955.
• Moore D, Amati-Bonneau P, Manes G, Hebrard M, Bocquet B, Quiles M, Piro-Mégy C, Teigell M, Delettre C, Rossel M, Meunier I, Preising M, Lorenz B, Carelli V, Chinnery PF, Yu-Wai-Man P, Kaplan J, Roubertie A, Barakat A, Bonneau D, Reynier P, Rozet JM, Bomont P, Hamel CP, Lenaers G (2015). Recessive mutations in RTN4IP1 cause isolated and syndromic optic neuropathies. Am J Hum Genet 97:754-760.
• Cereso N, Pequignot M, Robert L, Becker F, De Luca V, Nabholz N, Rigau V, De Vos J, Hamel CP, Kalatzis V (2014). Proof of concept for AAV2/5-mediated gene therapy in iPSc-derived retinal pigment epithelium of choroideremia patients. Molecular Therapy - Methods and Clinical Development 1:14011.
• Manes G*, Meunier I*, Avila-Fernandez A, Banfi S, Le Meur G, Zanlonghi X, Corton M, Simonelli F, Brabet P, Labesse G, Audo I, Mohand-Said S, Zeitz C, Sahel JA, Weber M, Dollfus H, Dhaenens CM, Allorge D, De Baere E, Koenekoop RK, Kohl S, Cremers FPM, Hollyfield JG, Senechal A, Hebrard M, Bocquet B, Ayuso Garcia C, Hamel CP (2013). Mutations in IMPG1 cause vitelliform macular dystrophies. Am J Hum Genet 93:571-578.
• Meunier I, Sénéchal A, Dhaenens C-M, Arndt C, Puech B, Defoort-Dellhemmes S, Manès G, Chazalette D, Mazoir E, Bocquet B, Hamel CP (2011). Systematic screening of BEST1 and PRPH2 in Best disease and adult-onset vitelliform macular dystrophy: a rational for molecular screening. Ophthalmology 118, 1130-1136.
• Guignard TJ, Jin M, Péquignot MO, Li S, Chassigneux Y, Chekroud K, Guillou L, Richard E, Hamel CP, Brabet P (2010). FATP1 inhibits 11-cis retinol formation via interaction with the visual cycle retinoid isomerase RPE65 and lecithin:retinolacyltransferase. J Biol Chem 285:18759-18768.
• Hamel CP, Meunier I, Arndt A, Ben Salah S, Lopez S, Bazalgette C, Bazalgette C, Zanlonghi X, Arnaud B, Defoort-Delhemmes S, Puech B (2009). Extensive Macular Atrophy with Pseudodrusen-like appearance (EMAP), a new clinical entity. Am J Ophthalmol 147, 609-620.
• Delettre C, Lenaers G, Griffoin J-M, Gigarel N, Lorenzo C, Belenguer P, Pelloquin L, Grosgeorges J, Turc-Carel C, Perret E, Astarie-Dequeker C, Lasquellec L, Arnaud B, Ducommun B, Kaplan J, Hamel CP (2000). Nuclear gene OPA1 encoding a mitochondrial dynamin-related protein is mutated in dominant optic atrophy. Nature Genetics 26, 207-210.
• Marlhens F, Bareil C, Griffoin J-M, Zrenner E, Amalric P, Eliaou C, Liu S-Y, Harris E, Redmond TM, Arnaud B, Claustres M, Hamel CP (1997).  Mutations in RPE65 cause Leber’s congenital amaurosis.  Nature Genetics 17, 139-141.