APBD and the Deep Intronic GBE1 Gene Mutation
Adult Polyglucosan Body Disease (APBD) is a recessive disorder - meaning that two copies of the mutated GBE1 gene (one from each parent) are required to cause the disease.
What is the intronic mutation I’ve heard about?
For many years, doctors identified patients who appeared to have APBD but seemed to only have one copy of a mutated GBE1 gene. These patients were referred to as “manifesting heterozygotes.”
The mutation that our scientists could identify was relatively easy to find because it is carried in a gene exon. However, unknown to the researchers at that time, there was also a separate mutation located inside the second gene’s intron, a part of the gene that is much harder to examine. The two mutations, one in an exon and the other in an intron, were working together to cause APBD.
This intronic mutation in the GBE1 gene, referred to as the “deep intronic” mutation, was discovered by Columbia University researcher H. Orhan Akman, Ph.D. and was published in JAMA Neurology in 2015. We are proud to say that Dr. Akman’s preclinical research was supported by the APBD Research Foundation.
Several intronic mutations have been discovered in GBE1. However, patients who have the “deep intronic” mutation identified by Dr. Akman may see the following wording on their genetic report:
c.2053-3358_2053-3350 delinsTGTTTTTTACATGACAGGT
c.2053-3358_2053-3350delins19 (Intronic)
c.2053-3358_2053-3350 delinsTGTTTTTTACATTACAGGTIVS15+5289_5297delGTGTGGTGGinsTGTTTTTTACATGACAGGT
To date, the deep intronic variant has only been found in a heterozygous state, meaning only one of the two GBE1 gene copies carries the mutation. The other copy of the GBE1 gene has been found to have an exon mutation. Researchers have theorized that having the intronic mutation in a homozygous state, or having two copies of it, is not compatible with life.
What is the therapy being developed for APBD patients who have the deep intronic mutation?
In 2025, the n-Lorem Foundation announced a potential antisense oligonucleotide (ASO) treatment for APBD patients with the deep intronic mutation. This announcement accompanied the publication of a research paper outlining their work to understand the impact of the mutation and screen candidate ASOs to treat APBD in these patients.
ASOs are a type of gene therapy consisting of short strands of DNA or RNA that are designed to specifically target the mutation in an affected gene copy - for APBD, the deep intronic mutation. As a therapy, ASOs can correct the gene blueprint to “fix” the protein that’s being produced or prevent an incorrect protein from being made. The nature of the “fix” will depend on the design of the ASO and the impact of the mutation that it is targeting.
Do you have (or think you may have) the deep intronic GBE1 mutation?
Have questions? To learn more about the n-Lorem Foundation’s ASO therapy in development, contact our Research Manager, Lindsay Gill, Ph.D. at lindsay@apbdrf.org.
Created November 24, 2025