EU-funded researchers have conducted the first successful trials of an innovative gene therapy to treat a rare and debilitating metabolic disorder, using a small and innocuous virus as a carrier for genetic information to correct the functioning of liver and muscle cells.
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The GLYCODIS3 project laid the foundations for a potential cure for glycogen storage disease type III (GSD III). This currently incurable genetic disorder causes generalised muscle deterioration. Triggered by excess accumulation of energy-storing glycogen molecules, the symptoms of GSD III can only currently be alleviated by patients following a strict diet of frequent meals high in carbohydrates to keep their blood sugar levels elevated, slowing but not stopping disease progression.
In new proof-of-concept laboratory trials, GLYCODIS3 researcher Giuseppe Ronzitti, head of the metabolic diseases laboratory at Genethon in France, demonstrated it is possible to modify the genes responsible for causing GSD III. The modifications enable glycogen to be cleared from muscle cells, thereby restoring muscle strength and helping to keep blood sugar in circulation.
The gene expression changes were achieved by encoding an adeno-associated virus, a small virus infectious to humans that is not known to have harmful effects, as a carrier for the gene therapy. Because the virus can only carry genetic information equivalent to around 5 000 base pairs of DNA, the researchers successfully engineered a novel dual-vector system that would carry different sets of genetic instructions separately and recombine once inside the target cells.
Adeno-associated viruses are currently the vectors of choice for gene therapy treatments and have been used in promising human trials of liver gene transfer therapies to treat haemophilia, and eye gene transfer to treat congenital blindness. The work of Ronzitti and his team, which has led to five patents and numerous scientific publications, has further expanded the potential, not only for treating GSD III but several other neuromuscular disorders.
GLYCODIS3, which was supported by the EUs Marie Skłodowska-Curie Individual Fellowships programme, has led to a number of follow-up projects that aim to continue the development of adeno-associated virus gene therapy for GSD III toward clinical use.