HCR.20.038 – ASO treatment for Neurodevelopmental Disorders

Route: Personalised medicine: the individual at the centre

Cluster question: 083 How do neurological, psychiatric, and mental disorders arise, and how can we prevent, mitigate, or cure them?

Approximately 1% of children are born with severe neurodevelopmental disorders (NDDs) for which there is currently no disease-modifying therapy. However, because NDDs are frequently caused by identifiable pathogenic mutations, a unique therapeutic opportunity has emerged from recent developments in molecular biology, with the potential to revolutionize the treatment of this entire group of disorders.

Antisense oligonucleotides (ASOs) can bind and modulate mutant RNA transcripts, and thereby prevent their pathogenicity. ASOs readily enter cells after targeted delivery, offering high therapeutic potential for NDDs. Antisense oligonucleotide treatment of Spinal Muscular Atrophy is life-saving, and trials are underway for Amyotropic Lateral Sclerosis, Huntingtons Disease and Angelman Syndrome. Unfortunately however, ultrarare mutations are historically understudied, despite being a major etiological class of pathogenicity underlying NDDs.

Here we propose a standardized platform to develop personalized treatments using induced pluripotent stem cells (iPSCs) obtained from patients with ultrarare mutations pathogenic for a neurodevelopmental disorder. We will assess the impact of these mutations on iPSC-derived neurons using robust validated state-of-the-art assays. Furthermore, we will design customized ASOs specific for defined ultrarare NDD pathogenic mutations to guide selection of lead candidates for advanced secondary (3D organoid) and tertiary (in vivo transplantation) screening as candidate disease modifying treatments in humans.


Anti-sense oligo nucleotides, genetic neurodevelopmental disorders, iPS, mouse model

Other organisations

Leiden Universitair Medisch Centrum (LUMC), Radboud Medical Center (RUMC)


Organisation Erasmus MC (EMC)
Name Prof. dr. Y. (Ype) Elgersma
E-mail y.elgersma@erasmusmc.nl
Website https://encore-expertisecentrum.nl