Prevention of hydrocephalus with a small oligonucleotide.

Hydrocephalus is one of the most common pediatric neurological disorders and is associated with monogenic syndromes. Untreated hydrocephalus has a high mortality rate, and current treatment involves surgical implantation of a shunt or third ventriculostomy, both of which have complex follow-up care. Molecular therapies to treat or prevent hydrocephalus might have widespread applications for monogenic syndromes but are currently underinvestigated. To determine whether oligonucleotides are a viable drug class to prevent hydrocephalus, we assessed a monogenic syndrome called Schinzel-Giedion syndrome (SGS). SGS is caused by increased SETBP1 protein due to heterozygous missense mutations in a degron motif of SETBP1. Mice that produce mutant human SETBP1 show hydrocephalus in over 50% of cases and do not live long. Treatment of mice with injections of antisense oligonucleotides targeting SETBP1 prevented or led to a significant reduction of hydrocephalus compared to mock-treated controls and improved long-term survival. These results suggest that hydrocephalus is preventable for a monogenic syndrome with an oligonucleotide intervention.