(MRC DTP) Induced pluripotent stem cell model of genetic autism

Autism Spectrum Disorder (ASD) is a highly heritable polygenic neurodevelopmental disorder, with early childhood onset and population prevalence of 1%. The neurobiology of ASD is poorly understood which impedes treatment discovery. There is intense international interest in understanding the neural basis of ASD in order to identify targets for biological treatments. However, direct study of the brain/ neurons is impossible in humans. This proposal is to develop an in vitro human pluripotent stem cell disease model of Neurofibromatosis Type 1(NF1), a single-gene syndromic model of ASD. NF1 is the commonest autosomal dominant neurodevelopmental disorder with birth incidence of 1:2700. Around 80% children with NF1 have learning disabilities and behavioural impairments including ASD. Mice carrying heterozygous null mutation of the Nf1 gene demonstrate the behavioural phenotype analogous to human NF1 and have provided mechanistic understanding of the underlying neurobiology. The primary defect is known to reside in the neurons; impaired NF1 function leads to disinhibition of the Ras/MAPKinase pathway, increased GABA mediated inhibition and impairments in long-term potentiation and synaptic function. Targeted treatments such as Simvastatin and Lamotrigine reverse the NF1 associated cognitive impairments in Nf1+/- mice but translational clinical trials in humans have so far been unsuccessful, with two failed multicentre RCTs of statins in children with NF1.

The aim of the proposal is to use induced pluripotent stem cells (iPSCs) to understand the neurobiology of ASD in NF1. Using NF1 as a monogenic ASD model, we will derive iPSCs from children with NF1+ASD, differentiate them to GABAergic neurons and use them for testing hypotheses generated from animal models. Since iPSCs can be scaled up to provide a platform for drug screening studies in NF1 and autism we will identify targets for drug testing and initiate medium through-put screens to carry out preliminary tests for efficacy. CRISPR Cas9 gene editing will be used to correct the defect and validate the phenotype in isogenic lines. Insights gained from studying NF1 ASD can be applied to ‘common ASD’ as many genetic variants associated with common ASD have functional expression on the Ras/MAPK pathways. Human iPSCs provide a more relevant model system than rodents and have the potential to make a significant scientific contribution to understanding autism as well as to reducing the number of animals in NF1 and autism research.

http://www.msca.manchester.ac.uk/
http://www.hpscale.manchester.ac.uk/
http://www.marm.manchester.ac.uk/
http://www.manchester.ac.uk/nwescc