Scientists at St. Jude Children’s Research Hospital have discovered that the following effects can be reversed: HNRNPH2Related neurodevelopmental disorders using antisense oligonucleotides (ASOs) in preclinical models. ASOs are short synthetic nucleic acid strands that target specific messenger RNAs. Published in scientific translational medicineresearchers showed that ASO blocks the production of abnormal HNRNPH2 protein. This increases expression of the closely related HNRNPH1 protein and alleviates multiple symptoms of the disease. This study provides important mechanistic data to support the advancement of this promising therapy into clinical studies.
HNRNPH2Associated neurodevelopmental disorders are X-linked genetic disorders with symptoms such as developmental delays, seizures, and motor, learning, and memory problems. Fewer than 200 cases have been confirmed so far, making it classified as extremely rare. There is currently no cure HNRNPH2This is in part because the disease’s rarity poses obstacles to both research and investment in treatment.
Since then HNRNPH2Since the associated disorder was first identified in patients 10 years ago, we have worked to better understand the mechanisms that cause this disease. Discovering the molecular basis of ASO at a time when it is emerging as an effective therapeutic technique was a remarkable convergence. The mechanisms we have identified are particularly amenable to ASO-based approaches, allowing us to intervene directly at the cause of the disease. This research is the next step in bringing real relief to patients and families who currently have no treatment options. ”
J. Paul Taylor, MD, PhD, corresponding author, St. Jude executive vice president, scientific director, chair of Cell and Molecular Biology, director of the Pediatric Translational Neuroscience Initiative
ASO therapy displaces HNRNPH2 and promotes HNRNPH1
Rather than changing the mutated gene itself, ASO therapy targets the messenger RNA produced by that gene. ASO target HNRNPH2 It flags RNA for destruction before abnormal proteins are made. Previous research from Taylor’s lab has shown that reducing HNRNPH2 protein levels promotes and compensates for increased levels of a closely related protein, HNRNPH1.
Both proteins are essential for RNA processing and may have overlapping roles during development. In particular, on the other hand, HNRNPH1 The expression level decreases as development progresses, but HNRNPH2 Expression persists until cells gradually become dependent. However, the mechanisms underlying this developmental transition and how HNRNPH2 influences it are unknown. HNRNPH1 His expression remained unclear. Furthermore, the researchers HNRNPH2Mutations cause the resulting protein to function abnormally (gain of function) or not function at all (loss of function).
In this study, researchers found that HNRNPH2 regulates. HNRNPH1 Expression by encouraging the gene expression system to skip important parts of the gene. This skip results in some problems. HNRNPH1 Messenger RNA must be disposed of promptly. Research shows that by suppressing mutations, HNRNPH2 Using ASO, this skip can be undone, resulting in HNRNPH1 Improvement of manifestation and symptoms.
“We hypothesized that there is an ASO strategy that significantly reduces HNRNPH2 levels and increases HNRNPH2 levels. HNRNPH1Expression should prove effective on both gain-of-function and loss-of-function mechanisms and improve symptoms. HNRNPH2 “This study tests that idea,” said lead author Dr. Ane Kolff of St. Jude’s Department of Cellular and Molecular Biology.
“We found that many symptoms improved after neonatal treatment with ASO in a preclinical model, and we also verified this effect after treatment in a slightly older boy,” Korff added. Due to genetic diagnosis, HNRNPH2Although associated disease may take years to develop, the results suggest that ASO therapy may prove beneficial even later in life.
These findings provide preclinical evidence that ASO strategies can be transformative for patients. HNRNPH2Related neurodevelopmental disorders and the entire ultra-rare disease community. “The first case of this disease was reported in 2016, and within 10 years we have moved from basic biology to designing translational therapies that have the potential to impact real patients,” said co-author Hong Joo Kim, Ph.D., of St. Jude’s Department of Cellular and Molecular Biology. “This is an amazing development, and it makes sense that research can move forward quickly to help patients.”
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St. Jude Children’s Research Hospital
Reference magazines:
Korff, A. others. (2026). Preclinical evaluation of antisense oligonucleotide therapy in mouse models HNRNPH2 Associated neurodevelopmental disorders. Science translational medicine. DOI: 10.1126/scitranslmed.adx3491. https://www.science.org/doi/10.1126/scitranslmed.adx3491
