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Treating the cognitive deficits associated with NF1 using the HCN channel agonist lamotrigine.

Projectomschrijving

Neurofibromatose is een erfelijke aandoening (1:2500 geboorten) die gepaard gaat met cognitieve problemen. Onderzoek in proefdieren heeft uitgewezen dat dit verholpen kan worden door lamotrigine. Een gerandomiseerde trial onder kinderen met NF1 is van start gegaan om te kijken of
lamotrigine inderdaad de cognitieve problemen kan verminderen. Helaas is de inclusie van alle benodigde patiënten nog niet gehaald en kan de data nog niet geanalyseerd worden. Momenteel worden buitenlandse centra benaderd om gezamenlijk de trial te af te ronden.

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Samenvatting van de aanvraag

The rare disorder Neurofibromatosis type 1 (NF1, 1:3000) is one of the most common monogenetic causes of cognitive disability. Besides a wide variability of cutaneous, endocrinologic, orthopedic problems and neurofibromas, individuals with NF1 are frequently impaired in cognitive, social, motor and emotional domains. As a consequence, 30% of the Dutch children with NF1 are not able to attend regular education. In addition, attention deficit hyper activity (ADHD) and autism spectrum disorders (ASD) are observed in 30-50% of children of NF1. Taken together, these problems have a large impact on the quality of life. Using several Nf1 mouse models, we have recently identified reduced HCN channel function as being responsible for the cognitive impairments in NF1 mice. We found that the HCN1 channel binds and is regulated by NF1, and that HCN function in Nf1 mice is reduced, causing increased excitability of inhibitory neurons. Moreover we found that the HCN agonist lamotrigine rescues the electrophysiological deficits (increased inhibition and decreased plasticity) in these mice, and most importantly, we found that lamotrigine administration to several mouse models of NF1 fully rescues the learning and motor impairments. We now propose to translate these findings to humans, by performing a small RCT proof-of-principle phase II trial, with IQ test as primary outcome measure, and behavioral and neurophysiological measures as secondary outcome measure. We believe that our 25 years of experience as national NF1 expertise center (with currently 400 children in active follow-up), our experience with cognitive trials, our close contact with the patient organization, and our use-patent on lamotrigine, gives us a very high chance to successfully develop this into a therapy

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Kenmerken

Projectnummer:
113303003
Looptijd: 100%
Looptijd: 100 %
2013
2016
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. Y. Elgersma
Verantwoordelijke organisatie:
Erasmus MC