A randomised, multicenter, double-blind,
placebo controlled, clinical trial using
desipramine in girls with Rett syndrome
Laurent Villard / Josette Mancini / Olivier Blin
Aix-Marseille University
Inserm
Marseille University Hospital
Rett syndrome : desipramine clinical trial
Pharmacological treatments

If a cellular deficit is identified

If abnormal levels of biological substances are associated with the disease

If existing drugs can prevent or restore these deficits
Rett syndrome : desipramine clinical trial
Pharmacological treatments

If a cellular deficit is identified
we identified a cellular basis to the respiratory deficits in the mouse model for RS
(Viemari, Roux et al., J Neurosci, 2005)

If abnormal levels of biological substances are associated with the disease
we measured abnormal levels of norepinephrine in the brainstem of the RS mouse
(Viemari, Roux et al., J Neurosci, 2005)

If existing drugs can prevent or restore these deficits
the use of desipramine, the most specific norepinephrine reuptake inhibitor, is able to
improve breathing and increase lifespan in a mouse model of Rett syndrome
(Roux et al., Eur J Neurosci, 2007)
Rett syndrome : desipramine clinical trial
Specific and progressive decrease of the number of Th-expressing neurones
 Are these cells abnormally generated during the development ?
 Is this type of neurones subject to programmed cell death ?
 Are these neurones loosing their ability to synthesize NE ?
Rett syndrome : desipramine clinical trial
Specific and progressive decrease of the number of Th-expressing neurones
 Are these cells abnormally generated during the development ?
No. The number of Th-neurones is normal when the mice are born.
 Is this type of neurones subject to programmed cell death ?
Extensive TUNEL labelling experiments reveal no apoptotic neurones.
 Are these neurones loosing their ability to synthesize NE ?
This is the most likely hypothesis.
Rett syndrome : desipramine clinical trial
Working to "boost" the remaining Th-expressing neurones
Rett syndrome : desipramine clinical trial
Using a pharmacological approach
Can we treat Mecp2-deficient mice ?
Yes.
With a norepinephrine reuptake inhibitor.
Which one ?
Desipramine (DMI).
Why ?
Because it is 30 time more potent to inhibit norepinephrine reuptake
than other available molecules.
Rett syndrome : desipramine clinical trial
Is this treatment efficient on the respiratory phenotype of the "Rett" mouse ?
Yes.
Their breathing pattern is stabilized during several weeks.
Is this treatment increasing the lifespan of the treated mice ?
Yes.
The lifespan of the treated animals is doubled.
(Roux et al., Eur. J. Neurosci., 2007)
Rett syndrome : desipramine clinical trial
What are the cellular consequences of this treatment ?
After 14 days of treatment with DMI, the KO-mice have a normal number of Th+ neurones !
There is no cellular proliferation.
H3-Ser10
Ki67
Could the cellular deficit be reversible ?
Rett syndrome : desipramine clinical trial
Can we use desipramine for a clinical trial ?
Yes because this molecule is authorized for human use.
Laboratory
Novartis
Brand name
Pertofran(UK, DE, FR) / Norpramin(US) / Nortimil(IT) / Deprexan(IL)
A phase II clinical trial was funded by the french ministery of health in spring 07
Title
Pilot study of desipramine effects on neuro-vegetative parameters of
children affected by Rett syndrome
Promotor
Marseille University Hospital
PI
Co-investigators
Prof. Josette Mancini (Pediatric Neurology, Marseille Children’s Hospital)
Dr Villard, Dr Roux, Pr Blin, Pr Dubus
Funding
French Ministery of Health
Amount awarded
500,000 $
Rett syndrome : desipramine clinical trial
Outline of our trial
Number of girls
36 (3x12)
Inclusion criteria
girl with Rett syndrome and MeCP2 mutation,
4 to 17 years old,
with breathing dysfunction
Exclusion criteria
males
patients with status epilepticus during the last 6 months
patients with documented cardiopathy
patients with liver or kidney deficits
Groups
1 – high dose
2 – low dose
3 – placebo
Treatment
6 months
Rett syndrome : desipramine clinical trial
Outline of our trial
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Clinical exam
X
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X
Blood test
X
ECG
Breathing rec.
X
X
X
X
X
X
X
X
X
X
X
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X
X
X
X
X
X
Video rec.
X
DMI dosage
X
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X
X
Evaluation
X
X
X
X
X
X
Rett syndrome : desipramine clinical trial
Outcomes
 Major criteria
one hour recording of breathing movements (Julu et al., 2001)
 Secondary criteria
cumulative duration of breathing defects
clinical tolerance
cardiac parameters
hand use and stereotypies (using video recording)
handicap severity (visual analogic scale)
Rett syndrome : desipramine clinical trial
Specific issues
We had to face 4 major issues :
1- desipramine was removed from the market in France.
2- clinical trials regulations have changed in Europe.
3- it is a clinical trial with children.
4- it is placebo-controled.
Rett syndrome : desipramine clinical trial
Heavy regulations = heavy delays !
2008
START
Protocol
AFFSSAPS
(FDA)
CPP
(IRB)
Ministery of Health
AFFSSAPS
(FDA)
Marseille University Hospital
(insurance + financial + administrative issues)
Funds awarded
2007
Rett syndrome : desipramine clinical trial
The function of MeCP2 will be difficult to restore in all cells (even in
neurones « only »)…
… but tailored pharmacological interventions could help alleviate a
number of symptoms in Rett syndrome.
Rett syndrome : desipramine clinical trial
Inserm U910 - Marseille
Laurent Villard
Jean-Christophe Roux
Emmanuelle Dura
Anne Moncla
www.germaco.net
Pediatric Neurology
(Children's Hospital Marseille)
Josette Mancini
Jean-Christophe Dubus
Center for Clinical Investigations
(CPCET)
Olivier Blin
Joëlle Micallef-Roll
www.afsr.net
www.eurorett.eu