Vasiliki Kalatzis PhD Human Genetics, HDR Life Sciences

Course and current status

Group Leader of "Gene Therapy of Retinal Dystrophies" within the Team 01 "Genetics and Therapy of Retinal and Optic Nerve Blindness" directed by Pr Christian Hamel at the Institute of Neurosciences of Montpellier.

Scientific summary

Current research

2011 to date – Gene therapy of retinal dystrophies using human cellular models.

The retina is particularly amenable to gene therapy because it is accessible via relatively non-invasive routes, it is small and enclosed allowing the use of small vector doses, and it is immuno-privileged due to sequestration from the systemic circulation by the blood-retina barrier. Moreover, retinal dystrophies are favourable candidates for gene therapy because they are often monogenic, have characteristic clinical signs allowing an early diagnosis, and progress slowly to blindness allowing a large therapeutic window. However, there are a growing number of retinal diseases that lack an appropriate animal model, which compromises their chances of one day reaching the stage of a clinical therapeutic trial.

The aim of our work is to find a viable alternative to palliate this lack of animal models. One way would be to perform preclinical studies on human cellular models of the diseased retina. The caveat is that it is impossible to obtain retinal cells directly from a patient. Therefore, our work is aimed at generating these cells via the intermediate of an innovative and powerful tool, induced pluripotent stem cells (iPSc). By taking skin fibroblasts from a patient affected with a specific retinal dystrophy, we can reprogram these cells into iPSc, which we can then differentiate into retinal cells such as the retinal pigment epithelium (RPE). In this way, we generate a human cellular model of the diseased retina.

We currently work on two different retinal dystrophies: choroideremia and retinitis punctata albescens. We have generated RPE for both of these disorders and by characterising the differences between control and patient RPE using a variety of techniques (molecular biology, cell biology, biochemical, imaging), we can obtain insights into the pathophysiology of the disease. Moreover, the generated RPE serves as a model for screening the efficiency of different therapeutics. By transducing this epithelium with a gene therapy vector carrying a healthy copy of the causative gene, we can obtain the proof of principle for a restoration of a normal phenotype, a first step towards clinical translation. Similarly, the generated RPE can be used to screen the efficiency of novel pharmacological agents. Finally, such a model generated in vitro represents a first step towards cell therapy approaches.


Previous research and selected publications

1998-2010 Cystinosis – a lysosomal storage disorder.Characterisation of a novel lysosomal transporter, pathophysiology studies and gene therapy studies using cellular and animal models.

- Maurice, T., Hippert, C., Serratrice, N., Dubois, G., Jacquet, C., Antignac, C., Kremer, E.J. & Kalatzis, V. (2009) Progressive cystine accumulation in the CNS of a cystinosis animal model results in severe age-related memory deficits. Neurobiol. Aging 30:987-1000.

- Hippert, C., Dubois, G., Morin, C., Disson, O., Ibanes, S., Jacquet, C., Schwendener, R., Antignac, C., Kremer, E.J. & Kalatzis, V. (2008) Gene transfer may be preventive but not curative for lysosomal storage due to a defective transporter. Mol. Ther. 16: 1372-1381.

- Kalatzis, V., Nevo N., Cherqui, S., Gasnier B. & Antignac, C. (2004) Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. Hum. Mol. Genet. 13: 1361-1371.

- Kalatzis, V., Cherqui, S., Antignac, C. & Gasnier B. (2001) Cystinosin, the protein defective in cystinosis, is a H+-driven lysosomal cystine transporter. EMBO J. 20: 5940-5949.


1993-1998 Branchial-Oto-Renal syndrome – a syndromic form of deafness. Identification of a novel family of transcription factor termed EYA with widespread developmental roles.

- Kalatzis, V., Sahly, I., El-Amraoui, A. & Petit, C. (1998) Eya1 expression in the developing ear and kidney: Towards the understanding of the pathogenesis of Branchio-Oto-Renal (BOR) syndrome. Dev. Dyn. 213: 486-499. 

 (Abdelhak, S., Kalatzis, V.,)*, Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., Bedbeder, P., Van Regemorter, N., Weissenbach, J. & Petit, C. (1997) A human homologue of the drosophila eyes absent gene underlies Branchio-Oto-Renal (BOR) syndrome and identifies a novel gene family. Nature Genet. 15: 157-164.  *contributed equally

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