Glycogen storage disease type III: research gaining momentum
Research into glycogen storage disease type III is gaining momentum, with advances across many areas and active contributions from Généthon and I-Stem.
Glycogen storage disease type III, also known as Cori-Forbes disease, is caused by mutations in the AGL gene, which encodes the glycogen debranching enzyme (GDE), leading to excessive glycogen accumulation in the muscles and liver. In recent years, researchers have made significant advances in understanding the mechanisms of the disease, developing new therapeutic approaches and improving patient follow-up.
Dynamic preclinical research
For several years, teams at Généthon and I-Stem, two AFM-Téléthon laboratories specialising respectively in gene therapy and stem cells, have been working together on several research programmes dedicated to glycogen storage disease type III.
● Development of induced pluripotent stem cells (iPSCs)
What are they?
iPSCs are obtained from adult cells that are “reprogrammed” in the laboratory to regain stem cell properties. They can then differentiate into different cell types, such as blood cells, muscle cells or neurons. When derived from patients with a disease, they can be used to model the condition, study its mechanisms and test new therapeutic approaches.
Researchers have created iPSC lines from cells taken from patients with glycogen storage disease type III or from cells modified using CRISPR/Cas9 technology.
→ Objective: to develop cellular models that reproduce abnormalities observed in the disease, such as abnormal glycogen accumulation, in order to better understand the underlying mechanisms and develop new treatments.
● A potential biomarker
The same researchers identified galectin-3 as a biomarker of the disease: its expression is increased in muscle biopsies from patients. Conversely, in mouse models of the disease treated with gene therapy, its expression decreases significantly.
→ Objective: to identify biomarkers that can be used to monitor disease progression or measure treatment efficacy.
● Different gene therapy approaches under investigation
What does this involve?
Gene therapy involves introducing genetic material into the body – in the case of glycogen storage disease type III, a functional AGL gene – using a viral vector (an adeno-associated virus, or AAV) to restore production of the missing enzyme and correct affected cells.
Because of its large size, the AGL gene is difficult to package into a single AAV vector. To overcome this obstacle, one approach involves simultaneously administering two viral vectors that together enable the complete GDE enzyme to be reconstituted. This strategy has proved effective in improving muscle and liver manifestations in mouse models of glycogen storage disease type III.
To prolong the effects of this approach, researchers at Généthon and I-Stem combined this dual-vector gene therapy with the simultaneous administration of rapamycin, an immunosuppressive drug already on the market. The combination produced synergistic effects in mouse models while limiting the immune response associated with the treatment.
The researchers are also investigating another approach involving a shortened but functional version of the GDE enzyme (mini-GDE), which can therefore be delivered using a single AAV vector. In mouse models of the disease, this gene therapy product reduced glycogen accumulation as well as muscle and cardiac involvement.
→ Objective: to develop safer and more effective gene therapy approaches with a view to future clinical trials in people with glycogen storage disease type III.
Across the Atlantic, a US research team is also investigating gene therapy in mouse models of glycogen storage disease type III, using a smaller bacterial GDE enzyme, pullulanase, or next-generation vectors known as MyoAAVs, which are designed to target muscles more effectively.
→ Objective: to overcome the constraints associated with the large size of the gene encoding GDE or to target muscles more effectively using lower doses of viral vectors.
Clinical studies and tools
Alongside this research, significant efforts are being made to improve patient follow-up.
● French care guidelines gaining international recognition
Published by the French National Authority for Health (HAS) in 2021, the French National Diagnosis and Care Protocol (PNDS) for glycogen storage disease type III provides healthcare professionals with guidance on optimal management and the care pathway for people with the disease. It gained international visibility through an article published in a scientific journal in July 2023.
→ Objective: to raise awareness of these recommendations and disseminate them more widely beyond France.
PNDS – Glycogen storage disease type III, 2021
Wicker C et al. 2023
● Analysis of data from the French registry
Established in 2013, the French registry of patients with glycogen storage disease type III collects muscle, metabolic, cardiac and nutritional data, among other information, from people living with the disease.
Analysis of muscle assessments – including the six-minute walk distance and Motor Function Measure (MFM) – carried out annually over 10 years in 46 registry participants aged 10 to 49 showed that walking ability is impaired compared with people without the disease. However, it remains broadly stable over time, although some patients experience progressive deterioration.
→ Objective: to monitor changes in motor function in order to identify patients at risk of decline at an early stage and preserve their walking ability and quality of life as effectively as possible.
● Potential benefits of exercise
Finally, a Spanish study assessed the effects of a three-month home-based physical activity programme combining endurance and strength training in nine patients with glycogen storage disease type III. The programme was well tolerated and was associated with improvements in fatigue, muscle strength and cardiorespiratory fitness.
→ Objective: to consider physical activity as a potential complement to nutritional management for people with glycogen storage disease type III.