Pompe disease is an autosomal recessive disorder caused by a deficiency of
acid α-
glucosidase (GAA; EC 3.2.1.20) and the resultant progressive lysosomal accumulation of
glycogen in skeletal and cardiac muscles.
Enzyme replacement therapy using recombinant human GAA (
rhGAA) has proven beneficial in addressing several aspects of the disease such as
cardiomyopathy and aberrant motor function. However, residual
muscle weakness,
hearing loss, and the risks of arrhythmias and
osteopenia persist despite
enzyme therapy. Here, we evaluated the relative merits of substrate reduction
therapy (by inhibiting
glycogen synthesis) as a potential adjuvant strategy. A phosphorodiamidate
morpholino oligonucleotide (PMO) designed to invoke exon skipping and
premature stop codon usage in the transcript for muscle specific
glycogen synthase (Gys1) was identified and conjugated to a
cell penetrating peptide (GS-PPMO) to facilitate PMO delivery to muscle. GS-PPMO systemic administration to Pompe mice led to a dose-dependent decrease in
glycogen synthase transcripts in the quadriceps, and the diaphragm but not the liver. An
mRNA response in the heart was seen only at the higher dose tested. Associated with these decreases in transcript levels were correspondingly lower tissue levels of muscle specific
glycogen synthase and activity. Importantly, these reductions resulted in significant decreases in the aberrant accumulation of lysosomal
glycogen in the quadriceps, diaphragm, and heart of Pompe mice. Treatment was without any overt toxicity, supporting the notion that substrate reduction by GS-PPMO-mediated inhibition of muscle specific
glycogen synthase represents a viable therapeutic strategy for
Pompe disease after further development.