Inhibiting or downregulating glycogen synthase by creating premature stop codons using antisense oligonucleotides

Abstract

The present disclosure relates to antisense oligonucleotides (AONs) for modulating the expression of glycogen synthase. AONs of the present disclosure may be useful in treating diseases associated with the modulation of the expression of the enzyme glycogen synthase, such as Pompe disease. Also provided by the present disclosure are compositions comprising AONs, as well as methods of down regulating mRNA coding for glycogen synthase, methods for reducing glycogen synthase in skeletal and cardiac muscle, and methods for treating Pompe disease.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 002,294, filed May 23, 2014, which is hereby incorporated by reference in its entirety.DESCRIPTION OF THE INVENTION[0002]Field of the Invention[0003]The present disclosure relates to antisense oligonucleotides (AONs) for modulating the expression of glycogen synthase. AONs of the present disclosure may be useful in treating diseases associated with the modulation of the expression of the enzyme glycogen synthase, such as Pompe disease. Also provided by the present disclosure are compositions comprising AONs, as well as methods of down regulating mRNA coding for glycogen synthase, methods for reducing glycogen synthase in skeletal and cardiac muscle, and methods for treating Pompe disease.SUMMARY OF THE INVENTION[0004]Pompe disease is an inherited disorder caused by the accumulation of glycogen in the body's cells. This buildup of glycogen in the b...

AI Technical Summary

Benefits of technology

[0008]Inhibiting the biosynthesis of glycogen is another potential means to treat patients with Pompe disease. So-called substrate reduction therapy is based on the inhibition of the main enzyme isoform responsible for building the glycogen polymer in skeletal muscle, glycogen synthase 1. Three methods have been reported that accomplish glycogen synthase 1 inhibition in Pompe mice: administration of a small interfering RNA (Douillard-Guilloux et al 2008); genetic knock down of the GSY1 gene in mice then crossed to Pompe mice (Douillard-Guilloux et al 2010); and inhibition of mTORC1 by administration of rapamycin (Ashe et al 2010). All three methods suppressed the accumulation of glycogen in Pompe mice. However, in the report by Ashe et al 2010 it was also reported that the administration of rapamycin and rec...

Problems solved by technology

Serious breathing problems can occur and children with this form of Pompe disease do not live past early childhood.

However, people with this form of the disease experience progressive muscle weakness, which ...

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