Molecular therapy : the journal of the American Society of Gene Therapy · 2026
Prevention of hydrocephalus with a small oligonucleotide.
СтатьяНазвание и аннотация: Перевод в очереди
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Antonyan Lilit, Bossini Linda, Zhang Xin, Ni Anjie, Hagel Marc-Daniel, Baronchelli Eva, Geusa Martina, Peng Huashan, Semenak Amelia, Fleming Peter, Alsuwaidi Shaima, Zhang Ying, Hu Beili, Fontana Diletta, Crippa Valentina, Codazzi Stefania, Macintosh Julia, Arriaga-Sierra Andres, Khan Basil, Hettige Nuwan, Jefri Malvin, Liang Yijing, Klein Stephanie, du Toit André, Phan Nhu T N, Schuppert Andreas, Zhou Yang, Piazza Rocco, Murai Keith, Jacquemont Sebastien, Sessa Alessandro, Ernst Carl
Аннотация
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.