Gene therapy for "MECP2-pathies"
Our research center, under the responsability of Prof. Nicolas Lévy (director of the center), is granted funds from the french muscular dystrophy association (AFM) to support a strategic program. The program funds several basic and translational projects for genetic diseases.
Our team will start a project aiming to the correction, using gene therapy, of the deficits observed in the Mecp2-deficient mouse. This work will be performed in collaboration with the group of Martine Barkats in the Institut de Myologie (Paris) and will take advantage of new adenoviruses.
Come back on these pages regularly to hear about this program.
RETTCURE 2009-2011
Development of new treatments for Rett syndrome.
The RettCure program is a project funded by the French National Research Agency
(ANR) with a budget of $ 700,000 for the period 2009-2011.
This programme is performed by our group in association with TARGEON Pharma, a company that develops new molecules to treat central nervous system diseases.
The objective of the RETTCURE program is to develop a new treatment for the respiratory (and possibly motor) symptoms of Rett Syndrome. To reach this goal, TARGEON will use its knowledge to identify and to synthesize the selected drug candidates, and our group will undertake the in-vivo and cellular evaluation using a mouse model for Rett syndrome. In case a candidate drug with satisfactory performances in the preclinical models is identified, the consortium will engage in a clinical “proof-of-concept” phase II trial as soon as possible.
A pharmacological intervention corrects part of the respiratory phenotype.
We demonstrated that is was possible to treat breathing troubles using an adequate pharmacological
intervention
(Roux et al., 2007).
Treatment with desipramine decreases the number of apneas in Mecp2-deficient mice.
Because our laboratory has demonstrated the existence of bioaminergic anomalies in a mouse model for Rett syndrome, we try to develop pharmacological approaches to alleviate specific aspects of the Rett syndrome phenotype. This is especially true for the breathing dysfunction which causes more than 25% of death in this disease. We used desipramine because it is the most specific norepinephrine reuptake inhibitor. We arbitrarily decided to initiate the treatment when the level reached 100 apneas per hour. We found that this threshold approximately corresponds to the major period of reduction of the number of TH-expressing neurons. Mecp2-deficient mice were divided in two groups, the first group was treated with desipramine and the second group with a placebo. In the placebo group, the number of apneas continues to increase until the death of the animals two weeks later (D+14, see below). In the group treated with desipramine, the breathing was stabilized and the number of apneas was strongly reduced in comparison to the placebo group (-75% after 3 days of treatment). The breathing pattern remains stable during approximately five weeks.
Desipramine treatment restores a normal number of tyrosine hydroxylase expressing neurons.
Our protocol leads to a partial correction of the cellular anomalies that we identified in the mouse model for Rett syndrome, indicating a significant degree of reversibility, a very important finding for the affected children. We know that the missing neurons in the Mecp2-deficient mice are not killed by apoptosis and that the treatment with desipramine does not induce cellular proliferation. Rather, we think that we observe less tyrosine hydroxylase expressing neurons in the Mecp2-deficient animals because some cells loose their phenotype. To test this hypothesis, we have counted the TH+ neurons after two weeks of treatment with desipramine. The treatment does not change the number of TH+ neurons in wildtype animals. On the contrary, a two weeks treatment allows the number of TH+ neurons to reach wildtype levels in Mecp2-deficient mice.
The lifespan of the treated animals is significantly extended.
We measured the impact of the treatment on the lifespan of the Mecp2-deficient mice treatment with desipramine. We used the same protocol as above but we continued the treatment as long as possible until the death of the treated animals. The first group of mice was not treated and lived approximately 57 days. The second group was treated with a placebo and had a similar lifespan. The third group, which was treated with desipramine, had a mean lifespan of 91 days +/- 11 days. This represents an increase of about 50% of the lifespan of the treated animals.
A clinical trial to treat respiratory dysfunction in Rett syndrome patients.
The work presented above is at the origin of a phase II clinical trial that has started in early 2009, promoted by Marseille University Hospital. It is the first example of a therapeutic intervention proposed to Rett syndrome children after basic research was performed in the mouse model of the condition.
The clinical trial is supervised by Professor Josette Mancini, from the Pediatric Neurology Department in La Timone Children's Hospital. The aim of this trial is to study the effect of desipramine on the neuro-vegetative parameters of children affected by Rett syndrome.