Antisense oligonucleotides reverse rare neurodevelopmental disorder in preclinical models

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 production of the aberrant HNRNPH2 protein. This consequently boosts 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 HNRNPH2-related neurodevelopmental disorder, in part because the rarity of this condition 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."

J. Paul Taylor, MD, PhD, corresponding author, St. Jude executive vice president, scientific director, Department of Cell & Molecular Biology chair and Pediatric Translational Neuroscience Initiative director

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. Notably, whereas HNRNPH1 expression decreases as development proceeds, HNRNPH2 expression persists until cells become progressively more dependent on it. However, the mechanism underlying this developmental transition and how HNRNPH2 influences HNRNPH1 expression remained unclear. Further, the researchers were unsure whether HNRNPH2mutations made the resulting protein work abnormally (gain of function) or not at all (loss of function).

In this study, the 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 hypothesized that an ASO strategy that substantially knocks down HNRNPH2 levels and increases HNRNPH1expression should prove effective for both gain-of-function and loss-of-function mechanisms and improve symptoms in the HNRNPH2 preclinical models," said first author Ané Korff, PhD, St. Jude Department of Cell & Molecular Biology. "This study tests that idea."

"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," Korff added. Since genetic diagnoses for HNRNPH2-related disorder may take several years, this result implies that ASO therapy may prove beneficial even later in life.

These findings provide preclinical evidence that an ASO strategy may be transformative for HNRNPH2-related neurodevelopmental disorder and the ultrarare disease community at large. "The first cases of this disorder were reported in 2016, and within 10 years, we went from basic biology to designing a translational therapy with the potential for real patient impact," said co-author Hong Joo Kim, PhD, St. Jude Department of Cell & Molecular Biology. "This is an amazing development, and it's meaningful that the work is quickly moving to help patients."