Inherited Optic Neuropathies: from diagnosis to treatments

Director of Research at CNRS : Guy Lenaers

(guy.lenaers @ univ-angers.fr)

guy.lenaers @ univ-angers.fr (guy.lenaers @ univ-angers.fr)

 guy.lenaers@inserm.fr (guy.lenaers @ inserm.fr)

Keywords: Mitochondrial dynamics, Inherited Optic Neuropathies, molecular diagnosis, therapies

State of the art and objectives

Inherited Optic Neuropathies (ION) are blinding diseases related to the loss of retinal ganglion cells, the neurons that transduce the visual information from the retina to the brain. In most cases, they are related to a mitochondrial defects. To date ION remain orphan diseases.

My work has three main objectives:

• Improve and broaden the molecular diagnosis in parallel to the clinical diagnosis and natural history, using ultimate sequencing technologies and the largest yet established worldwide ION DNA collections, and store results in FAIR databases;
• Unravel the pathophysiological mechanisms by analysing cellular models representative of the different mutated genes and mutations, and perform metabolomics studies on these cell models and plasma from patients to define biomarkers usable for ION diagnosis and treatment follow-up;
• Promote clinical trials using gene and pharmacological therapies, after obtaining the proofs of concept of these approaches on cellular and animal models.

Main results from the last 5 years:

• We have demonstrated that alterations of the mitochondrial dynamics is the crucial process involved in Dominant Optic Atrophy (DOA), by the identification of mutations in genes involved in mitochondrial fusion (OPA1, MFN2, AFG3L2, SPG7, YME1L) (OPA1: Roubertie, 2015; Chao de la Barca, 2017; Del Dotto, 2018; Jurkute, 2019; MFN2: Codron, 2016; AFG3L2: Charif, 2015) and fission (OPA3 and DRP1) (Gerber, 2017, 2018)

• We have demonstrated that alterations of the assembly of the complex I from the respiratory chain is one of the major culprit mechanism responsible for Recessive Optic Atrophy (ROA), as mutation in RTN4IP1, the most frequently mutated gene in ROA leads to a lack of CI holo-enzyme. (Angebault, 2015; Charif, 2017)

• We have provided the first evidences that gene therapy of OPA1 mutation is amenable in a mouse model of DOA, in order to prevent neurodegeneration of retinal ganglion neurons. Work is in progress to improve the molecular mechanism responsible for OPA1 rescue. (Sarzi, 2018)

• We have described a whole set of clinical inherited presentations affecting the vision (Grenier, 2016, Meunier, 2016) and/or audition (Buret, 2016; Salime 2017, Bousfiha, 2017; Bakhchane, 2015, 2017) and further mitochondrial diseases (Angebault, 2015, Charif, 2015; Colin, 2016; Bris, 2017; Roubertie, 2018; Felhi, 2019)

People involved

• Yannick Ledantec (Post-doc),
• Morgane LeMao (Engineer),
• Salim Khiati (Assistant Professor),
• Florian Beignon (PhD student),
• Cléis Beaulieu (PhD student),
• Aymane Bouzidi (PhD student),
• Ghita Amalou (PhD student),
• Patrizia Amati-Bonneau (Physician).

Main publications and patents from the 5 last years

• Neurologic Phenotypes Associated With Mutations in RTN4IP1 (OPA10) in Children and Young Adults.Charif M, et al. and Lenaers G. JAMA Neurol. 2018 Jan 1;75(1):105-113.
• A Plasma Metabolomic Signature Involving Purine Metabolism in Human Optic Atrophy 1 (OPA1)-Related Disorders. Bocca C, et al., and Lenaers G, Reynier P. Invest Ophthalmol Vis Sci. 2018;59(1):185-195.
• Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission. Gerber S, et al., and Lenaers G. Brain. 2017 Oct 1;140(10):2586-2596.
• Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy. Sarzi E, et al., and Lenaers G*, Müller A*. Hum Mol Genet. 2017;26(23):4764.
• Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies. Angebault C, et al. and Lenaers G. Am J Hum Genet. 2015 Nov 5;97(5):754-60.

Collaborations

In France

• Isabelle Meunier and Agathe Roubertie, Centre de références maladies rares neurosensorielles du CHU de Montpellier,
• Jean-Michel Rozet, Institut Imagine, Paris
• Catherine Vignal, Fondation Rothchild, Paris
• Sabien Defoort-delhemmes, CHRU Lille
• Xavier Zanlonghi, Clinique Jules Vernes, Nantes

International

• Patrick Yu-Wai-Man, Cambridge University, UK
• Valerio Carelli, University of Bologna, IT
• Bernd Wissinger, Eye Institute of Tuebingen, GE
• Marcella Votruba, University of Cardiff, Whales, UK
• AbdelHamid Barakat, Institut Pasteur de Casablanca, Morocco

Acknowledgements for the financial supports

• European E-Rare program, CNRS, INSERM, Université d’Angers.
• Patient organisations: UNADEV, VISIO, Ouvrir Les yeux, Kjer-France, JED, Fondation de France, Fondation pour la Recherche Médicale, Retina France.