Gene-targeted Therapy -- Anti-Sense Oligonucleotides -- Correct Intronic Variant and Restores GBE Enzyme Activity in Patients’ Cells
September 24, 2025
Researchers at the n-Lorem Foundation, Columbia University, and University of Washington have recently published an article showing the therapeutic potential for anti-sense oligonucleotides (ASOs) in recovering glycogen branching enzyme (GBE) activity in cells isolated from APBD patients who share the deep intronic mutation of the GBE1 gene. The published study is available as open-access from the scientific journal, Nucleic Acids Research.
The deep intronic mutation in GBE1 was discovered by Columbia University researcher H. Orhan Akman, Ph.D., an author on the recent manuscript, and published in JAMA Neurology in 2015. Through this work, Dr. Akman and colleagues were able to explain how some individuals who seemed to carry only one copy of a GBE1 mutation developed symptoms of APBD – termed “manifesting heterozygotes.” While these APBD patients only had one copy of a more common mutation, they carried a separate mutation in one of the introns, a part of the gene that is removed before the enzyme is made. This intronic mutation resulted in a shortened protein sequence and unstable enzyme that worked together with the other mutation to cause APBD.
The intronic mutation was discovered and initially evaluated by Dr. Akman (pictured), laying the groundwork for n-Lorem’s design of ASO treatments for intronic APBD patients.
The research team -- led by Dr. Stanley Crooke, co-founder of the n-Lorem Foundation -- investigated the consequences of the intronic variant. They discovered that the mutation resulted in the inclusion of extra material in the gene’s messenger RNA (mRNA), or the blueprint that directs the making of GBE. This change ultimately resulted in the mRNA being broken down by the cell and reducing the amount of GBE. After understanding the impact of the mutation, hundreds of ASOs were designed to address the consequences of the mutation and screened in cells from four patients with the intronic mutation. This process identified many highly efficacious ASO candidates that could increase the amount of GBE in the cells, bringing the n-Lorem APBD ASO studies one step closer to use in patients.
In a recent press release, the n-Lorem Foundation stated, “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. [...] n-Lorem continues to advance its lead ASO candidate in development.”
“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,” added n-Lorem.
Harriet Saxe, a member of the APBD Research Foundation’s Board of Directors, shared some history. “Following Dr. Akman’s discovery of the intronic mutation, a research grant from our Foundation supported the development of what we call our ‘intronic mouse model’ – a mouse model of APBD that replicates the deep intronic mutation. Another Foundation grant funded a follow-on, proof-of-concept study in the intronic mouse model to evaluate the therapeutic potential of ASOs in APBD associated with the intronic variant. n-Lorem’s recently published work provided the final piece of missing information needed for n-Lorem to create, design and develop a potential therapy that could alter the course of this disease. We are seeing the fruition of a decade of investments by patients, families, and other supporters. This is why we do what we do!”
Lindsay Gill, PhD, the APBD Research Foundation’s Research Manager, added, “The ability for an ASO to improve GBE enzyme activity in the cells of intronic patients is a very exciting finding. We have a dream scenario in translational science. Being able to take this work from identifying the mutation in patients, to proof-of-concept work in animal models, to the validation and testing of a viable therapy for patients is a major research success.”