Research, published in Nucleic Acids Research, identifies splice-modulating ASO that corrects the effects of a nano-rare GBE1 indel mutation, offering a potential path to treatment for a subset of APBD nano-rare patients
SAN DIEGO--(BUSINESS WIRE)--#ASO--n-Lorem, a nonprofit foundation, announced that Nucleic Acids Research has published its research that both characterized a pathogenic intronic splice variant of the glycogen branching enzyme (GBE1) gene and identified a splice-modulating antisense oligonucleotide (ASO) capable of restoring functional GBE1 protein in APBD patient cells. These data support a novel potential ASO treatment for nano-rare patients with same GBE1 pathogenic intronic splice variant. The findings in the paper, titled “Splice-modulating antisense oligonucleotides targeting a pathogenic intronic variant in Adult Polyglucosan Body Disease correct mis-splicing and restore enzyme activity in patient cells,” could offer, for the first time, a targeted therapy to restore gene function. The study, authored by n-Lorem scientist R. Thomas et al, was published in Nucleic Acids Research (NAR. 2025;53(13):gkaf658. https://doi.org/10.1093/nar/gkaf658).
Adult polyglucosan body disease (APBD) is a rare, progressive neurodegenerative disorder that typically appears in adulthood and worsens over time. Symptoms can include peripheral neuropathy, neurogenic bladder, fatigue, muscle weakness, spasticity, and autonomic dysfunction, with some patients also experiencing cognitive or visual impairment. APBD is caused by mutations in the GBE1 gene, which encodes the glycogen branching enzyme, an essential component in glycogen production. When GBE1 activity is reduced or lost, abnormally structured, insoluble glycogen accumulates in tissues as polyglucosan bodies, leading to widespread nerve and organ damage. Despite significant research in APBD, there are no effective disease-modifying therapeutic approaches for patients who suffer from APBD.
n-Lorem conducted this research to develop a therapeutic ASO approach for four APBD patients sharing a pathogenic GBE1 mutation. This deep intronic deletion–insertion (indel) mutation creates an abnormal splice site, producing a pseudoexon that encodes an unstable, truncated protein. The resulting loss of functional glycogen branching enzyme disrupts glycogen production, causing abnormal glycogen accumulation that progressively damages nerves and organs. Restoring GBE1 function with targeted ASOs could, for the first time, offer a way to halt disease progression in these patients.
“Our team’s decades of ASO experience and rigorous drug‑discovery expertise were critical when confronting a nano-rare GBE1 mutation,” said Konstantina Skourti-Stathaki, Ph.D., Senior Director, ASO Discovery and Research of the n-Lorem Foundation. “It’s precisely in these complex situations that our scientists excel by finding innovative, mutation-specific paths forward where none existed. In deeply characterizing this indel mutation, we not only delivered a promising therapeutic strategy for these patients but also advanced our collective understanding of APBD, reinforcing our conviction that precision medicines come from scientific inquiry and a focused mission to provide potential help to patients who are overlooked.”
Using long-read sequencing techniques, the n-Lorem scientists discovered several new features of the mutation, including that all four of the n-Lorem patients studied shared the same pathogenic indel, which differed from the previously reported indel sequence by one nucleotide. This was important finding as it indicated that all four patients could potentially be treated with the same ASO. The second important finding came from long-read RNA-seq analysis, which substantiated, for the first time, the transcriptional consequences of the mutation. These data are critical to design and discover optimal ASOs. Using high-throughput screening in patient cells, researchers identified several leading ASOs that effectively blocked the ectopic splice site, which resulted in increased levels of functional GBE1 enzyme. This was a critical proof-of-concept demonstrating that boosting GBE1 levels can effectively reduce glycogen storage to address the disease. n-Lorem continues to advance its lead ASO candidate in development. While one of the APBD patients sadly passed during the course of this work, n-Lorem remains committed to advancing the ASO to treatment, with the goal of helping the three remaining patients as soon as development is complete. Since the targeted mutation is the second most common mutation found in the GBE1 gene, the knowledge gained from this work will advance the community’s understanding of the mutation and could provide a therapeutic pathway for other APBD patients.
About n-Lorem
n-Lorem Foundation is a non-profit organization established to apply the efficiency, versatility and specificity of antisense technology to charitably provide experimental antisense oligonucleotide (ASO) medicines to treat nano-rare patients diagnosed with diseases that are the result of a single genetic defect unique to only one or very few individuals. Nano-rare patients describe a very small group of patients (1-30 worldwide) who, because of their small numbers, have few if any treatment options. n-Lorem Foundation was created to provide hope to these nano-rare patients by developing individualized ASO medicines, which are short strands of modified DNA that can specifically target the transcripts of a defective gene to correct the abnormality. The advantage of experimental ASO medicines is that they can be developed rapidly, inexpensively and are highly specific. To date, n-Lorem received over 330 applications for treatment with more than 160 nano-rare patients approved. n-Lorem was founded by Stanley T. Crooke, M.D., Ph.D., former chairman and CEO of Ionis Pharmaceuticals, who founded Ionis Pharmaceuticals in 1989 and, through his vision and leadership, established the company as the leader in RNA-targeted therapeutics. Follow us on Twitter, Facebook, LinkedIn and YouTube.
To learn more about n-Lorem’s mission at www.nlorem.org, and please consider giving to n-Lorem to bring hope, possibility and treatment options to these patients and families in need.
Contacts
n-Lorem Contact:
Amy Williford, Ph.D.
Executive Director of Communications and Donor Relations
amy.williford@nlorem.org
