EDUCATION and TRAINING
Pierre & Marie Curie University (UPMC) , Paris
2000: HDR (Habilitation to conduct scientific research) Mitochondrial diseases
1987: PhD Biochemistry and Life Sciences
1983: Master Biochemistry
1982: Bachelor Biochemistry and Life Sciences
Positions and Employment
2009: Research Director at the CNRS_DR2
1993: Permanent research position at the CNRS_CR1
1989: Permanent research position at the CNRS_CR2
Since 2003: Research group leader (Physipathology and therapy for eye diseases due to mitochondrial dysfunction) at the Institut de la Vision_CDR INSERM 968 UMR CNRS 7210 UPMC / CHNO des Quinze-Vingts (Therapeutics Department)
1995-2003: Research group leader (Mitochondrial biogenesis in the yeast S. Cerivisiae) at the UMR CNRS 8541 _Ecole Normale Supérieure of Paris (Department of Biology)
1993-1995: Post-Doctoral position, Unité de Recherches Hépatologiques _INSERM U49, Hôpital Pontchaillou, Rennes FRANCE
1990-1993: Post-doctoral Position, Dr. Douglas Wallace laboratory, Emory University_Atlanta, USA.
1984-1990 : PhD training, Institut de Pathologie Moléculaire, CNRS URA 1147, Faculté de Médecine Cochin-Port-Royal, Paris.
Retinal dystrophies caused by mitochondrial impairment, as other mitochondrial disorders, are inaccessible to therapy. Interestingly, three clinical trials for Leber Congenital Amaurosis due to RPE65 mutations were started in 2007. The data demonstrate that the technique is feasible, safe and leads to improvement of visual function, even at a relatively late stage of the disease. It is hugely encouraging to see that gene-replacement therapy for RPE65 driven by AAV vectors (Adeno-Associated Virus) can be effective; since it will pave the way for the development of gene therapy approaches for a broad range of eye disorders. Our most important goal are to: (1) understand the physiopathology of mitochondrial impairment leading to vision loss in experimental models; (2) provide a protective gene therapy to them using AAV2 vectors specifying the defective mitochondrial proteins.
The experimental models currently evaluated are:
1. A rat model of Leber Hereditary Optic Neuropathy (LHON) created by the optimized allotopic expression (expression of mitochondrial genes transferred to the nucleus) of the human mitochondrial ND4 gene harboring the G11778A substitution, responsible of ~70% of LHON cases (Ellouze et al., 2008). Eyes of these animals manifest retinal ganglion cell degeneration and optic nerve atrophy, the most prominent pathogenic events in LHON patients leading to vision loss due to respiratory chain complex I defect.
2. The Harlequin (Hq) mice which exhibit progressive photoreceptor and optic nerve degeneration leading to blindness which has been ascribed to a defective respiratory chain complex I activity due to the down-regulated expression of the AIF (Apotosis Inducing Factor) gene.
In these two models, we established the proof of principle that AAV2 vectors are effective in preventing optic atrophy and protecting respiratory chain complex I function without any harm or toxic effect in animals or their eyes.
These data will allow the development of a clinical trial for LHON. These clinical trials will evaluate safety but also a potential benefit in term of visual function and this should pave the way for clinical studies on other mitochondrial optic neuropathies such as Dominant Optic Atrophy or on devastating neurodegenerative disorders with mitochondrial etiology.