Glycogen synthase antisense oligonucleotides with enzyme replacement therapy reduces glycogen more effectively in the Pompe disease mouse


Translational Research

Poster Number: M253


Virginia Kimonis, M.D., University of California, Irvine, Angela Martin, MD, UC Irvine, Lan Weiss, MD,PhD, UC Irvine, Michele Carrer, Ionis Pharmaceuticals, Alyaa Shmara, MBCHB, UCI, Paymaan Jafar-nejad, Ionis Pharmaceuticals

Pompe disease is a progressive myopathy resulting from the deficiency of acid - glucosidase (GAA). Enzyme replacement therapy (ERT) with recombinant human (rh) GAA works well in alleviating the cardiomyopathy; however, many patients continue to have progressive muscle weakness from muscle glycogen accumulation produced by muscle glycogen synthase (GYS1). Previous studies have provided proof of principle that knockdown of GYS1 mRNA by antisense oligonucleotidereduced glycogen. To impart specificity for the muscle variant of the enzyme, antisense oligonucleotides (ASOs) targeting mouse Gys1 designed and previously screened in vitro and in vivo by Ionis Pharmaceuticals were assessed. In this report, we focused on the three ASOs to identify the most efficacious Gys1 ASO in Gaa-/- mice. The results from treatment with the three Gys1 ASOs We identified Gys1 ASO#3 as the most effective with 84% and 98% downregulation of Gys1 mRNA and GYS1 protein respectively, and 47% efficiency in clearing glycogen accumulation in quadriceps muscle of 1-month-old Gaa-/- Pompe mice. Combination therapy with Gys1 ASO#3 and ERT further reduced glycogen accumulation and effectively alleviated the massive autophagic buildup in Gaa-/- mice quadriceps to wild type mice level. The reversal of lysosomal and autophagic pathologies led to improved muscle function in treated Gaa-/- mice. Studies are currently ongoing with early treatment with ASOs in 4-day-old pups as potential monotherapy. Preliminary studies show that there is amelioration of the autophagic buildup These results provide proof of principle that ASOs inhibiting GYS1 can reduce glycogen in Pompe disease.