Progeria project

Team:

Xavier Nissan: Team leader (CECS)

Anne Laure Egesipe: Technician (CECS)

Alessandra Lo Cicero: Postdoc (CECS)

Lucile Hoch: Research Associate (CECS)

Celine Bruges: Technician (INSERM)

What is Progeria syndrome?

Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), is a rare, fatal genetic disease characterized by an appearance of accelerated aging in children. This syndrome is typically caused by mutations in codon 608 (G608G) of the LMNA leading to the production of a mutated form of Lamin A precursor called Progerin. In HGPS, Progerin accumulates in cells and causes progressive massives molecular defects including nuclear shape abnormalities, chromatin disorganization, DNA damages and delaay in cell proliferation.

Figure 1 : Lamin A/C staining in normal and Progeria cells

 

Our strategy at I-Stem

Recently two phase II clinical trials were initiated by treating HGPS patients with Farnesyltransferase inhibitors (FTIs) and/or the combination of Zoledronate and Pravastatin to prevent or delay the gravest infringements of the disease. Although these two studies have produced promising results, as well as in vitro and in vivo, there is currently no cure for HGPS patients.

In collaboration with Pr Nicolas Lévy, our team have generated induced pluripotent stem cells from progeria patients’ cells. Thanks to this unlimited and standardized biological ressource we are preparing a high throughput screening campain of pharmacological compounds in order to identify new treatments of this disease (Figure 2).

Figure 2: Pathological modeling of HGPS using pluripotent stem cells

 

In parrallel, we are also using these stem cells to investigate cellular and molecular mechanisms of HGPS. A first demonstration of this strategy was published in 2012 in Cell reports describing the role of miR-9 in the protecton of neurons from premature aging (Figure 3).

Figure 3: Identification of miR-9 as the sentinel of neurons in Progeria

 

Team’s publications:

Unique preservation of neural cells in Hutchinson- Gilford progeria syndrome is due to the expression of the neural-specific miR-9 microRNA. Nissan X, Blondel S, Navarro C, Maury Y, Denis C, Girard M, Martinat C, De Sandre-Giovannoli A, Levy N, Peschanski M. Cell Rep. 2012 Jul 26;2(1):1-9. Epub 2012 Jun 21.

[miR-9: the sentinel of neurons in progeria]. Blondel S, Navarro C, Lévy N, Peschanski M, Nissan X. Med Sci (Paris). 2012 Jun-Jul;28(6-7):663-6. Epub 2012 Jul 16. Review. French.

In vitro pathological modelling using patient-specific induced pluripotent stem cells: the case of progeria. Nissan X, Blondel S, Peschanski M. Biochem Soc Trans. 2011 Dec;39(6):1775-9. Review.

 

Collaborations:

Pr. Nicolas Lévy and Dr. Annachiara De Sandre Giovanelli, unité Inserm UMR S 910 Génétique médicale et génomique fonctionnelle, faculté de médecine Timone – Université de la Méditerranée

Dr. Alexandre Méjat, Laboratoire de biologie moléculaire de la cellule -UMR 5239- LBMC-ENS Lyon

Dr. Lino Ferreira, Center of Neurosciences and Cell Biology (CNC)/Biocant (Coimbra), Portugal