Lan Weiss, Michele Carrer, Alyaa Shmara, Angela Martin, Hong Yin, Pallabi Pal, Cheng Cheng, Lac Ta, Victoria Boock, Yasamin Fazeli, Mindy Chang, Marvin Paguio, Jonathan Lee, Howard Yu, John Weiss, Tamar R Grossman, Nina Raben, Paymaan Jafar-Nejad, Virginia Kimonis
{"title":"针对糖原合酶 1 的反义寡核苷酸对庞贝氏症小鼠模型骨骼肌的影响","authors":"Lan Weiss, Michele Carrer, Alyaa Shmara, Angela Martin, Hong Yin, Pallabi Pal, Cheng Cheng, Lac Ta, Victoria Boock, Yasamin Fazeli, Mindy Chang, Marvin Paguio, Jonathan Lee, Howard Yu, John Weiss, Tamar R Grossman, Nina Raben, Paymaan Jafar-Nejad, Virginia Kimonis","doi":"10.1002/ctm2.70314","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <p>Pompe disease (PD) is a progressive myopathy caused by the aberrant accumulation of glycogen in skeletal and cardiac muscle resulting from the deficiency of the enzyme acid alpha-glucosidase (GAA). Administration of recombinant human GAA as enzyme replacement therapy (ERT) works well in alleviating the cardiac manifestations of PD but loses sustained benefit in ameliorating the skeletal muscle pathology. The limited efficacy of ERT in skeletal muscle is partially attributable to its inability to curb the accumulation of new glycogen produced by the muscle enzyme glycogen synthase 1 (GYS1). Substrate reduction therapies aimed at knocking down GYS1 expression represent a promising avenue to improve Pompe myopathy. However, finding specific inhibitors for GYS1 is challenging given the presence of the highly homologous GYS2 in the liver. Antisense oligonucleotides (ASOs) are chemically modified oligomers that hybridise to their complementary target RNA to induce their degradation with exquisite specificity. In the present study, we show that ASO-mediated <i>Gys1</i> knockdown in the <i>Gaa<sup>−/−</sup></i> mouse model of PD led to a robust reduction in glycogen accumulation in skeletal muscle. In addition, combining <i>Gys1</i> ASO with ERT slightly further reduced glycogen content in muscle, eliminated autophagic buildup and lysosomal dysfunction, and improved motor function in <i>Gaa<sup>−/−</sup></i> mice. Our results provide a strong foundation for validation of the use of <i>Gys1</i> ASO, alone or in combination with ERT, as a therapy for PD. We propose that early administration of <i>Gys1</i> ASO in combination with ERT may be the key to preventative treatment options in PD.</p>\n </section>\n \n <section>\n \n <h3> Key points</h3>\n \n <div>\n <ul>\n \n <li>\n <p>Antisense oligonucleotide (ASO) treatment in a mouse model of Pompe disease achieves robust knockdown of glycogen synthase (GYS1).</p>\n </li>\n \n <li>\n <p>ASO treatment reduces glycogen content in skeletal muscle.</p>\n </li>\n \n <li>\n <p>Combination of ASO and enzyme replacement therapy (ERT) further improves motor performance compared to ASO alone in a mouse model of Pompe disease.</p>\n </li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9000,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70314","citationCount":"0","resultStr":"{\"title\":\"Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease\",\"authors\":\"Lan Weiss, Michele Carrer, Alyaa Shmara, Angela Martin, Hong Yin, Pallabi Pal, Cheng Cheng, Lac Ta, Victoria Boock, Yasamin Fazeli, Mindy Chang, Marvin Paguio, Jonathan Lee, Howard Yu, John Weiss, Tamar R Grossman, Nina Raben, Paymaan Jafar-Nejad, Virginia Kimonis\",\"doi\":\"10.1002/ctm2.70314\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <p>Pompe disease (PD) is a progressive myopathy caused by the aberrant accumulation of glycogen in skeletal and cardiac muscle resulting from the deficiency of the enzyme acid alpha-glucosidase (GAA). Administration of recombinant human GAA as enzyme replacement therapy (ERT) works well in alleviating the cardiac manifestations of PD but loses sustained benefit in ameliorating the skeletal muscle pathology. The limited efficacy of ERT in skeletal muscle is partially attributable to its inability to curb the accumulation of new glycogen produced by the muscle enzyme glycogen synthase 1 (GYS1). Substrate reduction therapies aimed at knocking down GYS1 expression represent a promising avenue to improve Pompe myopathy. However, finding specific inhibitors for GYS1 is challenging given the presence of the highly homologous GYS2 in the liver. Antisense oligonucleotides (ASOs) are chemically modified oligomers that hybridise to their complementary target RNA to induce their degradation with exquisite specificity. In the present study, we show that ASO-mediated <i>Gys1</i> knockdown in the <i>Gaa<sup>−/−</sup></i> mouse model of PD led to a robust reduction in glycogen accumulation in skeletal muscle. In addition, combining <i>Gys1</i> ASO with ERT slightly further reduced glycogen content in muscle, eliminated autophagic buildup and lysosomal dysfunction, and improved motor function in <i>Gaa<sup>−/−</sup></i> mice. Our results provide a strong foundation for validation of the use of <i>Gys1</i> ASO, alone or in combination with ERT, as a therapy for PD. We propose that early administration of <i>Gys1</i> ASO in combination with ERT may be the key to preventative treatment options in PD.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Key points</h3>\\n \\n <div>\\n <ul>\\n \\n <li>\\n <p>Antisense oligonucleotide (ASO) treatment in a mouse model of Pompe disease achieves robust knockdown of glycogen synthase (GYS1).</p>\\n </li>\\n \\n <li>\\n <p>ASO treatment reduces glycogen content in skeletal muscle.</p>\\n </li>\\n \\n <li>\\n <p>Combination of ASO and enzyme replacement therapy (ERT) further improves motor performance compared to ASO alone in a mouse model of Pompe disease.</p>\\n </li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":10189,\"journal\":{\"name\":\"Clinical and Translational Medicine\",\"volume\":\"15 4\",\"pages\":\"\"},\"PeriodicalIF\":7.9000,\"publicationDate\":\"2025-04-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70314\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical and Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70314\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70314","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease
Pompe disease (PD) is a progressive myopathy caused by the aberrant accumulation of glycogen in skeletal and cardiac muscle resulting from the deficiency of the enzyme acid alpha-glucosidase (GAA). Administration of recombinant human GAA as enzyme replacement therapy (ERT) works well in alleviating the cardiac manifestations of PD but loses sustained benefit in ameliorating the skeletal muscle pathology. The limited efficacy of ERT in skeletal muscle is partially attributable to its inability to curb the accumulation of new glycogen produced by the muscle enzyme glycogen synthase 1 (GYS1). Substrate reduction therapies aimed at knocking down GYS1 expression represent a promising avenue to improve Pompe myopathy. However, finding specific inhibitors for GYS1 is challenging given the presence of the highly homologous GYS2 in the liver. Antisense oligonucleotides (ASOs) are chemically modified oligomers that hybridise to their complementary target RNA to induce their degradation with exquisite specificity. In the present study, we show that ASO-mediated Gys1 knockdown in the Gaa−/− mouse model of PD led to a robust reduction in glycogen accumulation in skeletal muscle. In addition, combining Gys1 ASO with ERT slightly further reduced glycogen content in muscle, eliminated autophagic buildup and lysosomal dysfunction, and improved motor function in Gaa−/− mice. Our results provide a strong foundation for validation of the use of Gys1 ASO, alone or in combination with ERT, as a therapy for PD. We propose that early administration of Gys1 ASO in combination with ERT may be the key to preventative treatment options in PD.
Key points
Antisense oligonucleotide (ASO) treatment in a mouse model of Pompe disease achieves robust knockdown of glycogen synthase (GYS1).
ASO treatment reduces glycogen content in skeletal muscle.
Combination of ASO and enzyme replacement therapy (ERT) further improves motor performance compared to ASO alone in a mouse model of Pompe disease.
期刊介绍：
Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
