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. 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. IntroductionAcid α-glucosidase (GAA) is a lysosomal enzyme that catalyzes the breakdown of glycogen to glucose. Mutations in the GAA gene that lead to a reduction in the amount or activity of the enzyme are the molecular basis of Pompe disease (glycogen storage disease type II). This autosomal recessive metabolic myopathy results as a consequence of the progressive accumulation of undegraded glycogen, primarily in the lysosomes of cardiac and skeletal muscle. Patients with Pompe disease (incidence of ~1 in 40,000) present with a broad spectrum of disease severity that is inversely correlated with the amount of residual enzyme activity. Complete loss of enzyme activity results in an infantile presentation (so called “floppy babies”) with affected individuals rarely living beyond 2 years of age. Varying degrees of residual enzyme activity lead to a progressive myopathy in young adults as well as older individuals that is invariably fatal.1van der Ploeg AT Reuser AJ Pompe's disease.Lancet. 2008; 372: 1342-1353Abstract Full Text Full Text PDF PubMed Scopus (507) Google ScholarPompe disease is managed by periodic infusions of recombinant human GAA (rhGAA) that gained regulatory approval in 2006.2Myozyme Presecribing Infromation www.myozyme.comGoogle Scholar In clinical trials, the infusion of rhGAA improves cardiomyopathy, walking ability, prolongs survival,3Amalfitano A Bengur AR Morse RP Majure JM Case LE Veerling DL et al.Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial.Genet Med. 2001; 3: 132-138Abstract Full Text Full Text PDF PubMed Google Scholar,4Winkel LP Kamphoven JH van den Hout HJ Severijnen LA van Doorn PA Reuser AJ et al.Morphological changes in muscle tissue of patients with infantile Pompe's disease receiving enzyme replacement therapy.Muscle Nerve. 2003; 27: 743-751Crossref PubMed Scopus (82) Google Scholar,5Klinge L Straub V Neudorf U Voit T Enzyme replacement therapy in classical infantile pompe disease: results of a ten-month follow-up study.Neuropediatrics. 2005; 36: 6-11Crossref PubMed Scopus (101) Google Scholar,6Koeberl DD Kishnani PS Chen YT Glycogen storage disease types I and II: treatment updates.J Inherit Metab Dis. 2007; 30: 159-164Crossref PubMed Scopus (57) Google Scholar,7Kishnani PS Corzo D Nicolino M Byrne B Mandel H Hwu WL et al.Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease.Neurology. 2007; 68: 99-109Crossref PubMed Scopus (610) Google Scholar,8Nicolino M Byrne B Wraith JE Leslie N Mandel H Freyer DR et al.Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease.Genet Med. 2009; 11: 210-219Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar,9Kishnani PS Corzo D Leslie ND Gruskin D Van der Ploeg A Clancy JP et al.Early treatment with alglucosidase alpha prolongs long-term survival of infants with Pompe disease.Pediatr Res. 2009; 66: 329-335Crossref PubMed Scopus (226) Google Scholar and stabilizes pulmonary function in patients.10van der Ploeg AT Clemens PR Corzo D Escolar DM Florence J Groeneveld GJ et al.A randomized of alglucosidase alfa in Pompe's J Med. PubMed Scopus Google Scholar However, patients with enzyme therapy present with aspects of the der Ploeg AT Clemens PR Corzo D Escolar DM Florence J Groeneveld GJ et al.A randomized of alglucosidase alfa in Pompe's J Med. PubMed Scopus Google Scholar residual muscle and hearing loss are and the for and osteopenia Case LE et of long-term with infantile Pompe disease.Genet Med. 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In Pompe glycogen synthase was to in the skeletal muscle and in the heart to This was not to higher levels of mRNA and to an in the of the enzyme in these Pompe A V et of glycogen as an therapy for Pompe Full Text Full Text PDF PubMed Scopus Google Scholar However, were in the levels of glycogen synthase in the of Pompe mice to of levels are in skeletal and cardiac of Pompe mice with of was of to levels in of and Pompe mice that the levels to were in the quadriceps, diaphragm, and heart was for the of GS-PPMO mice as in the and to to to to GS-PPMO at of Pompe mice with GS-PPMO or the amount of glycogen synthase in the and diaphragm to levels Treatment the levels of glycogen synthase in the Pompe and at the higher dose dose of GS-PPMO affected the amount of glycogen synthase in the Pompe mice with rhGAA not the amount of glycogen synthase in the administration of GS-PPMO glycogen synthase activity in the skeletal muscle and heart of Pompe Pompe mice with GS-PPMO led to of the glycogen synthase activity in the A reduction of enzyme activity in the heart was only in Pompe mice at the higher dose of GS-PPMO an in activity was at the lower In these are with the mRNA and Pompe mice with rhGAA the dose glycogen synthase activity in the skeletal muscle but that in the heart to This response to treatment with the recombinant enzyme is with in Pompe J et acid alpha-glucosidase with at the metabolic and motor function in a of Pompe 2009; Full Text Full Text PDF PubMed Scopus Google synthase activity is in the and heart of Pompe mice with Glycogen synthase activity in the and heart of and Pompe mice was as in the and mice as in the and to to to to GS-PPMO at treatment with GS-PPMO accumulation of tissue glycogen in Pompe were to glycogen to the reductions in glycogen synthase levels and activity in Pompe mice resulted in a of lysosomal glycogen Pompe mice with GS-PPMO led to a dose-dependent decrease in glycogen accumulation in the and heart and a reduction to the in mice in the diaphragm at In the and diaphragm of Pompe mice with the levels of glycogen were to in mice. 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This was in the heart but only with the higher dose is to that with the of in the Pompe the administration of dose GS-PPMO further by Glycogen synthase activity is at the of that is by the is not treatment with GS-PPMO at a with GAA administration However, GS-PPMO at glycogen synthase activity in the heart to of glycogen synthase and activity in the heart is at the higher dose tested. This the that in the glycogen storage in the of rhGAA and GS-PPMO treatment glycogen in Pompe mice. of and diaphragm after treatment with rhGAA at in glycogen to Pompe mice. Treatment with GS-PPMO was at glycogen in the and diaphragm, the tissue to levels at the A of glycogen was in the of mice with rhGAA to levels in mice. 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However, the of for as a therapeutic for Pompe disease these Pompe patients with a of rhGAA and a glycogen synthase to the human GS-PPMO activity at and activity in skeletal muscle diaphragm, but was in the In rhGAA is at glycogen the heart skeletal that the merits of the treatment are and in is to the of GS-PPMO and is to a and of phosphorodiamidate morpholino were PMO were designed to to mRNA as to invoke exon skipping or inhibition as by PA and of mRNA with 2007; PubMed Scopus Google Scholar designed to in mRNA are as the to the of 2 the to the of the of exon the of exon the of exon to PMO the of exon was designed to by a to the codon of the of exon the of exon the of exon of a peptide to a morpholino of PMO to a peptide was as in and 2009; PubMed Scopus Google Scholar with the with the to as a was in B was in at a a of at peptide was to in of and to at for 2 was with and GS-PPMO were by a and the with a 2 and was several of in a with molecular of GS-PPMO was by in at and were in with the for the and of of and and by of PMO for mice were with and the muscle was as of and in of 2007; Google Scholar were with of 2 PMO and was with of and the with the muscle was using the of at and were 2 after and muscle and administration of and and mice were to the of substrate inhibition using were a of and at the of the to as a for the glycogen accumulation as a for the of the GS-PPMO was in and at or by 2 for a of and was in a of and and by 2 for the potential for a to mice were with at the dose of after the the mice were and in for in or in for was using a with was using the with and for and and were and using the were using J of and mRNA were of tissue were in of 2 2 acid and and using a and at were at for at and the and at were using the as by the of tissue were in and to a the were using a were with and the to a of and for at were with a for at and with an substrate as by the were using J of glycogen synthase and 2 were to synthase activity Glycogen synthase activity in tissue was using a as A M A A to glycogen synthase B 2005; PubMed Scopus Google Scholar A of of glycogen, and was in a for the was with and of the was a and at for was to and was using a Enzyme activity was by the amount of glycogen of of tissue glycogen glycogen levels were as J J et of of acid alpha-glucosidase to the and motor function of and Pompe 2008; PubMed Scopus Google Scholar using an the was and using a and with and glycogen was to the Glycogen levels were by the levels in the in the was in the of mice after the dose of was to for and at for was as and at In of in was by at using the clinical in to the and were mice for to in and for and of Scholar were and with and A the evaluated the for are as was with using of and A of was to IntroductionAcid α-glucosidase (GAA) is a lysosomal enzyme that catalyzes the breakdown of glycogen to glucose. Mutations in the GAA gene that lead to a reduction in the amount or activity of the enzyme are the molecular basis of Pompe disease (glycogen storage disease type II). This autosomal recessive metabolic myopathy results as a consequence of the progressive accumulation of undegraded glycogen, primarily in the lysosomes of cardiac and skeletal muscle. Patients with Pompe disease (incidence of ~1 in 40,000) present with a broad spectrum of disease severity that is inversely correlated with the amount of residual enzyme activity. Complete loss of enzyme activity results in an infantile presentation (so called “floppy babies”) with affected individuals rarely living beyond 2 years of age. Varying degrees of residual enzyme activity lead to a progressive myopathy in young adults as well as older individuals that is invariably fatal.1van der Ploeg AT Reuser AJ Pompe's disease.Lancet. 2008; 372: 1342-1353Abstract Full Text Full Text PDF PubMed Scopus (507) Google ScholarPompe disease is managed by periodic infusions of recombinant human GAA (rhGAA) that gained regulatory approval in 2006.2Myozyme Presecribing Infromation www.myozyme.comGoogle Scholar In clinical trials, the infusion of rhGAA improves cardiomyopathy, walking ability, prolongs survival,3Amalfitano A Bengur AR Morse RP Majure JM Case LE Veerling DL et al.Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial.Genet Med. 2001; 3: 132-138Abstract Full Text Full Text PDF PubMed Google Scholar,4Winkel LP Kamphoven JH van den Hout HJ Severijnen LA van Doorn PA Reuser AJ et al.Morphological changes in muscle tissue of patients with infantile Pompe's disease receiving enzyme replacement therapy.Muscle Nerve. 2003; 27: 743-751Crossref PubMed Scopus (82) Google Scholar,5Klinge L Straub V Neudorf U Voit T Enzyme replacement therapy in classical infantile pompe disease: results of a ten-month follow-up study.Neuropediatrics. 2005; 36: 6-11Crossref PubMed Scopus (101) Google Scholar,6Koeberl DD Kishnani PS Chen YT Glycogen storage disease types I and II: treatment updates.J Inherit Metab Dis. 2007; 30: 159-164Crossref PubMed Scopus (57) Google Scholar,7Kishnani PS Corzo D Nicolino M Byrne B Mandel H Hwu WL et al.Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease.Neurology. 2007; 68: 99-109Crossref PubMed Scopus (610) Google Scholar,8Nicolino M Byrne B Wraith JE Leslie N Mandel H Freyer DR et al.Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease.Genet Med. 2009; 11: 210-219Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar,9Kishnani PS Corzo D Leslie ND Gruskin D Van der Ploeg A Clancy JP et al.Early treatment with alglucosidase alpha prolongs long-term survival of infants with Pompe disease.Pediatr Res. 2009; 66: 329-335Crossref PubMed Scopus (226) Google Scholar and stabilizes pulmonary function in patients.10van der Ploeg AT Clemens PR Corzo D Escolar DM Florence J Groeneveld GJ et al.A randomized of alglucosidase alfa in Pompe's J Med. PubMed Scopus Google Scholar However, patients with enzyme therapy present with aspects of the der Ploeg AT Clemens PR Corzo D Escolar DM Florence J Groeneveld GJ et al.A randomized of alglucosidase alfa in Pompe's J Med. PubMed Scopus Google Scholar residual muscle and hearing loss are and the for and osteopenia Case LE et of long-term with infantile Pompe disease.Genet Med. Full Text Full Text PDF PubMed Scopus Google Scholar residual to delivery of the enzyme to or to the response to the of rhGAA conjugated with J et acid alpha-glucosidase with at the metabolic and motor function in a of Pompe 2009; Full Text Full Text PDF PubMed Scopus Google Scholar or to a of J et lysosomal of acid muscle glycogen in pompe PubMed Scopus Google Scholar with delivery to muscle and in In a that improves the of the enzyme and glycogen in Pompe mice is J M et recombinant human acid and glycogen reduction in a of Pompe PubMed Scopus Google Scholar therapy with recombinant GAA is J J et of of acid alpha-glucosidase to the and motor function of and Pompe 2008; PubMed Scopus Google LA et I/II of alpha-glucosidase gene therapy to the diaphragm for in Pompe disease: and PubMed Scopus Google reduction that the of glycogen represents therapeutic strategy for lysosomal storage merits of for and JM M N B to the et of the in the of type I disease: a Inherit Metab Dis. 2003; PubMed Scopus Google N M M M et al.A phase 2 of an substrate reduction therapy for disease type PubMed Scopus Google J D WL J et reduction the of enzyme therapy in a of PubMed Scopus (57) Google Scholar glycogen are by glycogen activity is by of and in a by the Glycogen and and PubMed Scopus Google Scholar Glycogen synthase enzyme activity in Pompe mice is and activity is by treatment to lower glycogen levels in skeletal A V et of glycogen as an therapy for Pompe Full Text Full Text PDF PubMed Scopus Google Scholar Pompe mice with glycogen in skeletal and in with rhGAA infusions glycogen levels in skeletal muscle and diaphragm treatment not glycogen in the an well by to the levels of the in cardiac An of as a substrate reduction was that glycogen synthase was to with the enzyme However, a was that the dose of at glycogen accumulation was evaluated the of glycogen synthase for muscle glycogen levels in Pompe mice. muscle glycogen synthase activity is the of of the gene In glycogen synthase activity is by of the gene and enzyme glycogen as a of for in for has that is to a dose of a phosphorodiamidate morpholino oligonucleotide (PMO) for the of skipping and a V J exon skipping for and PubMed Scopus Google Scholar PMO dose to is conjugated to a cell penetrating peptide in and 2009; PubMed Scopus Google Scholar strategy to exon skipping of the mRNA for the of transcript with reductions in the skeletal muscle Pompe mice with a a specific in exon of mRNA (GS-PPMO) led to a dose-dependent reduction of the transcript in skeletal muscle and heart but not the transcript in liver. the glycogen synthase was in skeletal muscle and heart and glycogen synthase activity was to that of mice. glycogen accumulation was in skeletal the was in the these results that substrate reduction by of skeletal muscle glycogen synthase represents a adjuvant therapy for Pompe
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