St. Jude Scientists Use Synthetic Nucleic Acids to Reverse Ultrarare Neurodevelopmental Disorder in Preclinical Models

Researchers at St. Jude use antisense oligonucleotides to reverse symptoms of HNRNPH2-related disorder in preclinical models, paving the way for clinical trials.

By: AXL Media

Published: Apr 23, 2026, 9:44 AM EDT

Source: Information for this report was sourced from St. Jude Children's Research Hospital

Targeting the Molecular Root of Ultrarare Disease

A research team at St. Jude Children’s Research Hospital has achieved a significant breakthrough in treating HNRNPH2-related neurodevelopmental disorder, an ultrarare genetic condition with fewer than 200 confirmed cases worldwide. Utilizing antisense oligonucleotides, or ASOs, scientists were able to intervene at the molecular level to halt the production of toxic proteins. According to corresponding author Dr. J. Paul Taylor, the discovery of the disease's molecular basis coincided perfectly with the emergence of ASO technology. This convergence has allowed researchers to design a therapy that addresses the disease at its source, providing a potential roadmap for clinical trials in a field where no treatment currently exists.

Mechanistic Synergy Between HNRNPH1 and HNRNPH2

The therapeutic strategy hinges on a unique relationship between two closely related proteins: HNRNPH1 and HNRNPH2. Both are essential for RNA processing, but while HNRNPH1 levels naturally decline during development, HNRNPH2 expression typically persists. The study revealed that the mutated HNRNPH2 protein actively suppresses HNRNPH1 by forcing the cellular machinery to skip critical genetic segments, causing HNRNPH1 messenger RNA to be destroyed. By deploying ASOs to flag the mutated HNRNPH2 for destruction, the researchers successfully removed this suppression. This allowed HNRNPH1 levels to rebound and compensate for the missing or dysfunctional HNRNPH2, effectively restoring cellular balance.

Symptom Reversal in Developing and Juvenile Models

The preclinical investigation demonstrated that ASO therapy could reverse multiple symptoms of the disorder, including motor deficits and cognitive impairments. First author Dr. Ané Korff noted that while the most dramatic results were observed following neonatal treatment, the therapy also proved effective in older juvenile models. This finding is particularly significant for the patient community, as genetic diagnoses for ultrarare disorders often take several years to finalize. The ability to reverse existing symptoms in older subjects suggests that the therapeutic window for ASO intervention may remain open much later into childhood than previously anticipated.