A pharmacological intervention corrects part of the respiratory phenotype
We recently 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.
Since 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.
Starting 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 should start in summer 2008, promoted by Marseille University Hospital. It will be 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, head of 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. It is a world premiere since there is no other trial proposed anywhere after basic research was performed in the mouse model for Rett syndrome.