Breakthrough in Treating a Rare Neurodevelopmental Disorder
Scientists at St. Jude Children's Research Hospital have reported a significant advance in the search for a treatment for HNRNPH2-related neurodevelopmental disorder. Their research, published in the journal Science Translational Medicine, demonstrates that antisense oligonucleotides (ASOs) reversed the effects of the disorder in preclinical models.
The work provides mechanistic data to support advancing this therapy to clinical studies.
How the Potential Therapy Works
ASOs are short synthetic nucleic acid strands designed to target specific messenger RNA. In this study, researchers found that ASOs targeting the HNRNPH2 gene successfully blocked the production of an aberrant protein. This blockade had a secondary, beneficial effect: it increased the expression of a related protein, HNRNPH1.
The increase in HNRNPH1 expression was associated with a reduction of multiple disorder symptoms in the models. The treatment showed promise at different stages of development.
"We hypothesized that an ASO strategy that substantially knocks down HNRNPH2 levels and increases HNRNPH1 expression should prove effective... This study tests that idea," said first author Ané Korff, PhD.
Researchers stated that treatment with ASOs reversed symptoms when administered neonatally and also showed effect when administered to slightly older juvenile models.
Understanding the Disorder
HNRNPH2-related neurodevelopmental disorder is an X-linked genetic condition. Symptoms include developmental delay, seizures, and problems with movement, learning, and memory. Fewer than 200 cases have been confirmed, classifying it as an ultrarare disease. There is currently no cure.
A Decade of Progress Toward a Treatment
Since the disorder was first identified in patients a decade ago, researchers have worked to understand its mechanisms. This latest study marks a pivotal step toward a tangible therapy.
"Since HNRNPH2-related disorder was first identified in patients a decade ago, we have worked to better understand the mechanisms driving the disease... This study represents the next step in bringing real relief to patients and families for whom treatment options are currently nonexistent," said corresponding author J. Paul Taylor, MD, PhD.
Co-author Hong Joo Kim, PhD, highlighted the speed of this translational research: "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."
Research Collaboration and Support
The study's authors include researchers from St. Jude Children's Research Hospital and Ionis Pharmaceuticals. The work was supported by the National Institutes of Health (R35NS097974) and the American Lebanese Syrian Associated Charities (ALSAC).