Rett's Syndrome Clinical Trial
Official title:
A Phase 1 Clinical Study to Assess Safety and Efficacy of Oral Fingolimod (FTY720) in Children With Rett Syndrome.
The Trial Objective is to assess safety and efficacy of oral fingolimod (FTY720) in children older than 6 years with Rett Syndrome. So far there is no established treatment for children with Rett Syndrome. Therefore a positive result in terms of safety and first indications of efficacy would path the way to a phase II clinical study with more patients to further test the hypothesis that fingolimod treatment may slow down the regression of motor and language skills.
Rett syndrome is a neurodevelopmental disorder characterized by normal early psychomotor
development followed by the loss of psychomotor and acquired purposeful hand skills and the
onset of stereotyped movement of the hands and gait disturbance. The gene was discovered in
1999 and the disease was found to be caused by a mutation of the methyl-CpGbinding protein 2
(MeCP2). However, in many ways this clinically peculiar condition remains a mystery, with no
clear correlations between the gene mutation and abnormal biological markers, neuropathology
and/or unique clinical symptoms and signs.
Rett syndrome is an X-linked (Xq28) dominant postnatal severe neurodevelopmental disorder
which is the second most common cause for genetic mental retardation in girls and the first
pervasive disorder with a known genetic basis. Its incidence is between 1/10,000-15000 live
births. The classical variant is characterized by apparently normal development for the first
6-18 months accompanied usually with early deceleration of head growth, followed by period of
regression of motor and language skills, hand stereotypes, seizures, autonomic dysfunction
and other neurological and related symptoms.
Repeated observations and experiments of the mouse models in several laboratories led to the
appreciation of the role of BDNF in the disease pathophysiology. BDNF is a neurotrophic
factor playing a major role in neurogenesis, neuronal survival, differentiation, and
maturation during early development as well as in synaptic function and plasticity throughout
life. Abnormalities in BDNF homeostasis are believed to contribute to the neurological
phenotype and pathophysiology in part of the symptoms in methyl-CpG binding protein 2(Mecp2)
null mice that show progressive deficits in its expression during the symptomatic stage.
FTY720 (Gilenya) is an orally active modulator of four of the five sphingosine-1
phosphate(S1P) receptors. FTY720 acts as 'super agonist' on the S1P receptor on thymocytes
and lymphocytes, inducing uncoupling/internalization of that receptor.
A local study group (Yves-Alain Barde) found that FTY720 increases the levels of brain
derived neurotrophic factor and improves symptoms of mice lacking MeCP2. In addition the
volume of the striatum seemed to be higher (4 week old mice were treated in 4 days intervals
with 0.1mg/kg body weight intraperitoneally).
Based on these results we intend to perform a phase I clinical,study to assess safety and
efficacy of oral fingolimod (FTY720) in children with Rett Syndrome. Children will be
included if being older than 6 years of age, fulfilling diagnostic criteria of Rett Syndrome
in clinical Stages II -IV and having parents that do agree.
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