CV Science

Guy LENAERS Director

Course and current status

PhD in 1990, HDR in 2003.

Director of the MitoLab team (60 persons) involved in mitochondrial diseases and medicine

Director of the MitoVasc Unit (MitoLab + CarMe teams = 120 persons)

Co-Manager of the NeuroMitOmics axis (220 persons) at the interface of the University Hospital and University of Angers, addressing all Neurological and Mitochondrial diseases, by a multi-OMICs approach.

Scientific summary

For the last 10 years, I dedicated my work to the genetics, pathophysiology and therapies of inherited mitochondrial diseases, with a special focus on those affecting the optic nerve, leading to blindness. In 2015, I moved from Montpellier Institute of Neurosciences to Angers University and University Hospital to develop a Mitochondrial Medicine Research Centre with a 3.000.000 € grant from the Region Pays de la Loire. Today, the MitoLab team that I manage is the largest team dedicated to mitochondrial diseases in France, which grew from 20 persons in 2015 to more than 50 in 2023. The team was accredited by the CNRS and INSERM in 2017 and renewed in January 2022. I will keep the management of this team until December 2027 and have endorsed the direction of the MitoVasc Unit (including 2 teams: MitoLab and CarMe, accounting for 120 persons) from January 2022 to December 2027.

Importantly, in the last years, my research projects reached 2 preclinical proofs of concept, now patented, which allowed the design and implementation of clinical trials for DOA patients carrying OPA1 mutations, one based on a pharmacological compound, and one based on a gene therapy using a trans-splicing mechanism of OPA1 pre-mRNAs, which has been licenced by a private company. These clinical perspectives represent major achievements of my carrier related to the discovery of OPA1 gene in 2000 and published in Nature Genetics, with clinical perspectives that are now taken over back to the patients by medical doctors. This situation provides me the opportunity to face a new major scientific challenge concerning an unpreceded aspect of mitochondrial physiology, which consists in the control of mitochondrial thermogenesis.

10 best publications in the last 10 years.

For the last 10 years, I have published 140 papers. My h-index is 45 and i10-index is 124, and citation index above 11.000.

- The multiple facets of mitochondrial regulations controlling cellular thermogenesis. Beignon F, … Lenaers G. Cell Mol Life Sci. 2022 Sep, 20,79(10):525. doi: 10.1007/s00018-022-04523-8. 

An exhaustive review on the cellular processes participating to mitochondrial thermogenesis

- Autosomal recessive Leber Hereditary Optic Neuropathy, a new Neuro-Ophthalmo-Genetic paradigm. Lenaers G, … Rozet JM. Brain April 2023 (online ahead of print)

Sensibilization of the Neuro-Ophthalomology community to a new mode of transmission of the LHON

- Dominant optic atrophy: Culprit mitochondria in the optic nerve. Lenaers G, … Wissinger B. Prog Retin Eye Res. 2021 Jul;83:100935. doi: 10.1016/j.preteyeres.2020.100935.

An extending review on DOA, published in the most prestigious journal of ophthalmology.

- Dominant ACO2 mutations are a frequent cause of isolated optic atrophy. Charif M, … Lenaers G. Brain Commun. 2021 Apr 7;3(2):fcab063. doi: 10.1093/braincomms/fcab063. eCollection 2021.

Heterozygous mutations in ACO2 are the second cause of DOA and question the former DOA pathophysiological paradigm related to mitochondrial dynamic alterations.

- Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy. Charif M, … Lenaers G. Mol Neurodegener. 2021 Feb 25;16(1):12. doi: 10.1186/s13024-021-00431-w.

First heterozygous variants identified in MIEF1 are leading to a late-onset peculiar DOA.

-Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy. Charif M, … Lenaers G. Neurol Genet. 2020 May 20;6(3):e428. doi: 10.1212/NXG.0000000000000428.

Identification of molecular and clinical cross talks between spastic paraplegia, spinocerebellar ataxia and DOA presentations.

 - OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mouse model. Sarzi E, … Lenaers G, Delettre C. Sci Rep. 2018 Feb 6;8(1):2468. doi: 10.1038/s41598-018-20838-8

An OPA1 “classical” gene therapy approach provides significant but restricted benefits in a mouse model of the disease.

- Neurologic Phenotypes Associated With Mutations in RTN4IP1 (OPA10) in Children and Young Adults. Charif M, … Lenaers G. JAMA Neurol. 2018 Jan 1;75(1):105-113. doi: 10.1001/jamaneurol.2017.2065.

World-wide overview off all clinical paediatric presentations associated to RTN4IP1 variants.

- Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission. Gerber S, … Lenaers G. Brain. 2017 Oct 1;140(10):2586-2596. doi: 10.1093/brain/awx219

Surprising identification of DNM1L variants in DOA patients, as DNM1L and OPA1 have opposite function on mitochondrial network dynamics.

- Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies. Angebault C, … Lenaers G. Am J Hum Genet. 2015 Nov 5;97(5):754-60. doi: 10.1016/j.ajhg.2015.09.012.

Identification of the first RTN4IP1 variants as the most common form of recessive optic atrophy.

Patents:

- Metabolic signature and use thereof for the diagnosis of Glaucoma (# 18305375.0-1118; 2018)

- A trans-splicing OPA1 gene therapy process for the treatment of DOA patients related to OPA1 mutations (# EP22199015.3; 2022).