Scientists at St. Jude Children's Research Hospital have found they can reverse the effects of HNRNPH2-related neurodevelopmental disorder using antisense oligonucleotides (ASOs) in preclinical models. ASOs are short synthetic nucleic acid strands that target specific messenger RNA. Published in Science Translational Medicine, the researchers showed that ASOs block the production of the aberrant HNRNPH2 protein. This consequently boosts the expression of the closely related HNRNPH1 protein, reducing multiple symptoms of the disorder. The work provides vital mechanistic data to support the advancement of this promising therapy to clinical studies.
HNRNPH2-related neurodevelopmental disorder is an X-linked genetic condition whose symptoms include developmental delay, seizures, and problems with movement, learning, and memory. Fewer than 200 cases have been confirmed to date, classifying it as ultrarare. There is currently no cure for this disorder, in part because its rarity presents an obstacle to both research and therapeutic investment.
"Since HNRNPH2-related disorder was first identified in patients a decade ago, we have worked to better understand the mechanisms driving the disease. It was a remarkable convergence that we discovered its molecular basis just as ASOs were emerging as an effective therapeutic technology. The mechanism we identified was especially well suited to an ASO-based approach, allowing us to intervene directly at the source of the disease. This study represents the next step in bringing real relief to patients and families for whom treatment options are currently nonexistent."
ASO therapy kicks out HNRNPH2, boosts HNRNPH1
Rather than altering the mutated gene itself, ASO therapies target the messenger RNA produced from that gene. The ASOs targeting HNRNPH2 flag its RNA for destruction before an aberrant protein can be made. Previous studies from Taylor's lab have shown that reducing HNRNPH2 protein levels encourages the closely related protein, HNRNPH1, to step up to compensate. Both proteins are vital to RNA processing and likely play overlapping roles during development.
In this study, researchers found that HNRNPH2 regulates HNRNPH1 expression by promoting gene expression systems to skip a vital part of the gene. This skip causes any resulting HNRNPH1 messenger RNA to be promptly scrapped. The research showed that by silencing the mutated HNRNPH2 with an ASO, this skip could be reversed, leading to increased HNRNPH1 expression and improved symptoms.
"We found that many symptoms were reversed after neonatal treatment with an ASO in the preclinical models and also verified this effect after treatment in slightly older juveniles," noted first author Ané Korff, PhD. These findings provide preclinical evidence that an ASO strategy may be transformative for the ultrarare disease community at large.
