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We will review the available treatment options. We examine newly approved treatments as well as upcoming therapies in this condition. We also provide commentary on the unmet needs in clinical management and research for this disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Recent Findings<\/jats:title>\n                    <jats:p>\n                      In March 2015, Pompe disease was added to the Recommended Uniform Screening Panel (RUSP) and since then a number of states have added Pompe disease to their slate of diseases for their Newborn Screening (NBS) program. Data emerging from these programs is revising our knowledge of incidence of Pompe disease. In 2021, two randomized controlled trials involving new forms of enzyme replacement therapy (ERT) were completed and one new product is already FDA-approved and on the market, whereas the other product will come up for FDA review in the fall. Neither of the new ERT were shown to be superior to the standard of care product,\n                      <jats:italic>alglucosidase<\/jats:italic>\n                      . The long-term effectiveness of these newer forms of ERT is unclear. Newer versions of the ERT are in development in addition to multiple different strategies of gene therapy to deliver GAA, the gene responsible for producing acid alpha-glucosidase, the defective protein in Pompe Disease. Glycogen substrate reduction is also in development in Pompe disease and other glycogen storage disorders.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>There are significant unmet needs as it relates to clinical care and therapeutics in Pompe disease as well as in research. The currently available treatments lose effectiveness over the long run and do not have penetration into neuronal tissues and inconsistent penetration in certain muscles. More definitive gene therapy and enzyme replacement strategies are currently in development and testing.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11940-022-00736-1","type":"journal-article","created":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T08:02:45Z","timestamp":1659600165000},"page":"573-588","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Pompe Disease: a Clinical, Diagnostic, and Therapeutic Overview"],"prefix":"10.1007","volume":"24","author":[{"given":"David","family":"Stevens","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shadi","family":"Milani-Nejad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1230-0188","authenticated-orcid":false,"given":"Tahseen","family":"Mozaffar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,8,4]]},"reference":[{"issue":"9646","key":"736_CR1","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1016\/S0140-6736(08)61555-X","volume":"372","author":"AT van der Ploeg","year":"2008","unstructured":"van der Ploeg AT, Reuser AJ. Pompe\u2019s disease. Lancet. 2008;372(9646):1342\u201353.","journal-title":"Lancet"},{"key":"736_CR2","unstructured":"Engel AG. Acid maltase deficiency of adult life. Trans Am Neurol Assoc. 1969;94(250\u20132)."},{"issue":"3","key":"736_CR3","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1093\/brain\/93.3.599","volume":"93","author":"AG Engel","year":"1970","unstructured":"Engel AG. Acid maltase deficiency in adults: studies in four cases of a syndrome which may mimic muscular dystrophy or other myopathies. Brain. 1970;93(3):599\u2013616.","journal-title":"Brain"},{"issue":"5","key":"736_CR4","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1097\/WCO.0b013e32834aa38d","volume":"24","author":"V Nigro","year":"2011","unstructured":"Nigro V, Aurino S, Piluso G. Limb girdle muscular dystrophies: update on genetic diagnosis and therapeutic approaches. 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Int J Neonatal Screen. 2020;6(1):11.","journal-title":"Int J Neonatal Screen"},{"issue":"1","key":"736_CR13","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1186\/s13023-021-02146-z","volume":"16","author":"T Sawada","year":"2021","unstructured":"Sawada T, Kido J, Sugawara K, Momosaki K, Yoshida S, Kojima-Ishii K, et al. Current status of newborn screening for Pompe disease in Japan. Orphanet J Rare Dis. 2021;16(1):516.","journal-title":"Orphanet J Rare Dis"},{"key":"736_CR14","doi-asserted-by":"crossref","unstructured":"\u2022 Chien YH, Lee NC, Huang HJ, Thurberg BL, Tsai FJ and Hwu WL. Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. J Pediatr. 2011;158(6):1023\u201327.e1. This paper details the efforts made by investigators in Taiwan to introduce NBS for a number of lysosomal disorders, including Pompe Disease. Taiwan was the first country in the world to introduce NBS for Pompe Disease and had to contend with issues with false positives from pseudodeficiency, that has a much higher prevalence in South East Asian populations.","DOI":"10.1016\/j.jpeds.2010.11.053"},{"key":"736_CR15","doi-asserted-by":"crossref","unstructured":"Yang CF, Liu HC, Hsu TR, Tsai FC, Chiang SF, Chiang CC, et al. A large-scale nationwide newborn screening program for Pompe disease in Taiwan: towards effective diagnosis and treatment. Am J Med Genet A. 2014;164a(1):54\u201361.","DOI":"10.1002\/ajmg.a.36197"},{"issue":"1","key":"736_CR16","doi-asserted-by":"publisher","first-page":"73","DOI":"10.3233\/JND-140045","volume":"2","author":"JC Deenen","year":"2015","unstructured":"Deenen JC, Horlings CG, Verschuuren JJ, Verbeek AL, van Engelen BG. The epidemiology of neuromuscular disorders: a comprehensive overview of the literature. 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It found the prevalence of LOPD to be 1% but another 1% of patients were found to have pseudodeficiency.","DOI":"10.1212\/NXG.0000000000000623"},{"issue":"5","key":"736_CR21","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1590\/0004-282X20130022","volume":"71","author":"LC Werneck","year":"2013","unstructured":"Werneck LC, Lorenzoni PJ, Kay CS, Scola RH. Muscle biopsy in Pompe disease. Arq Neuropsiquiatr. 2013;71(5):284\u20139.","journal-title":"Arq Neuropsiquiatr"},{"key":"736_CR22","doi-asserted-by":"crossref","unstructured":"\u2022 Ni\u00f1o MY, Wijgerde M, de Faria DOS, Hoogeveen-Westerveld M, Bergsma AJ, Broeders M, et al. Enzymatic diagnosis of Pompe disease: lessons from 28 years of experience. Eur J Hum Genet. 2021;29(3):434\u201346. 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Ann Transl Med. 2019;7(13):283.","journal-title":"Ann Transl Med"},{"issue":"5","key":"736_CR39","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1097\/01.gim.0000218152.87434.f3","volume":"8","author":"PS Kishnani","year":"2006","unstructured":"Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006;8(5):267\u201388.","journal-title":"Genet Med"},{"key":"736_CR40","doi-asserted-by":"crossref","unstructured":"\u2022 Harlaar L, Hogrel JY, Perniconi B, Kruijshaar ME, Rizopoulos D, Taouagh N, et al. Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease. Neurology. 2019;93(19):e1756-e1767. This paper critically analyzes the long term experience with enzyme replacement therapy and how the treatment loses its benefit over a period of years, often starting at 36 months. The loss of benefits was across the board in all functional elements.","DOI":"10.1212\/WNL.0000000000008441"},{"issue":"2","key":"736_CR41","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.nmd.2020.12.001","volume":"31","author":"GK Papadimas","year":"2021","unstructured":"Papadimas GK, Anagnostopoulos C, Xirou S, Michelakakis H, Terzis G, Mavridou I, et al. Effect of long term enzyme replacement therapy in late onset Pompe disease: a single-centre experience. Neuromuscul Disord. 2021;31(2):91\u2013100.","journal-title":"Neuromuscul Disord"},{"key":"736_CR42","unstructured":"\u2022\u2022 Diaz-Manera J, Kishnani PS, Kushlaf H, Ladha S, Mozaffar T, Straub V, et al. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial. Lancet Neurol. 2021;20(12):1012\u201326. This paper reports the results of the Phase 3 randomized controlled trial of avalglucosidase alfa vs. alglucosidase alfa in treatment naive patients with LOPD. This was a true head-to-head comparison of avalglucosidase alfa, a newly designed ERT, with more M6P moeities, to alglucosidase alfa, the standard of care in LOPD since 2010. The results show that avalglucosidase alfa was non-inferior to alglucosidase alfa, but there were trends in some outcome measures that showed avalglucosidase alfa to be significantly better than alglucosidase alfa. This resulted in FDA approval of avalglucosidase alfa for treatment of all forms of Pompe Disease in 2021."},{"key":"736_CR43","unstructured":"\u2022\u2022 Schoser B, Roberts M, Byrne BJ, Sitaraman S, Jiang H, Lafor\u00eat P, et al. Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial. Lancet Neurol. 2021;20(12):1027\u201337. This paper reports the results of the Phase 3 randomized controlled trial of cipaglucosidase alfa in combination with miglustat, a stabilizer of the enzyme, vs. alglucosidase alfa and a placebo in treatment naive patients with LOPD. This was comparison of cipaglucosidase alfa, a newly designed ERT with through clonal selection of rhGAA with CHO-cell derived M6P and bis-M6P moieties, to alglucosidase alfa, the standard of care in LOPD since 2010. The results show that avalglucosidase alfa was non-inferior to alglucosidase alfa, but there were trends in some outcome measures that showed cipaglucosidase alfa to be significantly better than alglucosidase alfa. This new drug will go up for FDA review in Fall 2022."},{"key":"736_CR44","doi-asserted-by":"crossref","unstructured":"\u2022 Baik AD, Calafati P, Zhang X, Aaron NA, Mehra A, Moller-Tank S, et al. Cell type-selective targeted delivery of a recombinant lysosomal enzyme for enzyme therapies. Mol Ther. 2021;29(12):3512\u201324. A very interesting paper that describes a two-step process being developed by Regeneron for treatment of Pompe Disease. They also use a gene therapy approach to create a liver-depot to create endogenous supply of these ERT that are conjugated with monoclonal antibodies to CD63 and ITGA7 to ensure maximal delivery to muscle and cardiac tissue.","DOI":"10.1016\/j.ymthe.2021.08.020"},{"issue":"12","key":"736_CR45","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1016\/j.molmed.2019.08.005","volume":"25","author":"Z Zhou","year":"2019","unstructured":"\u2022 Zhou Z, Austin GL, Shaffer R, Armstrong DD, Gentry MS. Antibody-mediated enzyme therapeutics and applications in glycogen storage diseases. Trends Mol Med. 2019;25(12):1094\u2013109.\u00a0A good review of new efforts to develop enzyme replacement therapies conjugated with monoclonal antibodies to allow better delivery to skeletal muscle and cardiac tissue.","journal-title":"Trends Mol Med"},{"issue":"13","key":"736_CR46","doi-asserted-by":"publisher","first-page":"287","DOI":"10.21037\/atm.2019.04.67","volume":"7","author":"G Ronzitti","year":"2019","unstructured":"Ronzitti G, Collaud F, Laforet P, Mingozzi F. Progress and challenges of gene therapy for Pompe disease. Ann Transl Med. 2019;7(13):287.","journal-title":"Ann Transl Med"},{"issue":"4","key":"736_CR47","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1006\/mthe.2002.0563","volume":"5","author":"E Ding","year":"2002","unstructured":"Ding E, Hu H, Hodges BL, Migone F, Serra D, Xu F, et al. Efficacy of gene therapy for a prototypical lysosomal storage disease (GSD-II) is critically dependent on vector dose, transgene promoter, and the tissues targeted for vector transduction. Mol Ther. 2002;5(4):436\u201346.","journal-title":"Mol Ther"},{"issue":"13","key":"736_CR48","doi-asserted-by":"publisher","first-page":"288","DOI":"10.21037\/atm.2019.05.02","volume":"7","author":"PS Kishnani","year":"2019","unstructured":"Kishnani PS, Koeberl DD. Liver depot gene therapy for Pompe disease. Ann Transl Med. 2019;7(13):288.","journal-title":"Ann Transl Med"},{"issue":"1","key":"736_CR49","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202113968","volume":"14","author":"M Eggers","year":"2022","unstructured":"Eggers M, Vannoy CH, Huang J, Purushothaman P, Brassard J, Fonck C, et al. Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity. EMBO Mol Med. 2022;14(1): e13968.","journal-title":"EMBO Mol Med"},{"issue":"1","key":"736_CR50","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3233\/JND-190426","volume":"7","author":"SM Salabarria","year":"2020","unstructured":"Salabarria SM, Nair J, Clement N, Smith BK, Raben N, Fuller DD, et al. Advancements in AAV-mediated gene therapy for Pompe disease. J Neuromuscul Dis. 2020;7(1):15\u201331.","journal-title":"J Neuromuscul Dis"},{"issue":"6","key":"736_CR51","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1089\/hum.2012.250","volume":"24","author":"BK Smith","year":"2013","unstructured":"\u2022 Smith BK, Collins SW, Conlon TJ, Mah CS, Lawson LA, Martin AD, et al. Phase I\/II trial of adeno-associated virus-mediated alpha-glucosidase gene therapy to the diaphragm for chronic respiratory failure in Pompe disease: initial safety and ventilatory outcomes. Hum Gene Ther. 2013;24(6):630\u201340 This seminal paper details the development of gene therapy that could be delivered intramuscularly to different skeletal muscles in infantile and late-onset Pompe Disease, including laparoscopic injections into the diaphragm. The paper also discusses the initial experiences with this construct.","journal-title":"Hum Gene Ther"},{"issue":"10","key":"736_CR52","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2014.57","volume":"3","author":"NP Clayton","year":"2014","unstructured":"Clayton NP, Nelson CA, Weeden T, Taylor KM, Moreland RJ, Scheule RK, et al. Antisense oligonucleotide-mediated suppression of muscle glycogen synthase 1 synthesis as an approach for substrate reduction therapy of Pompe disease. Mol Ther Nucleic Acids. 2014;3(10): e206.","journal-title":"Mol Ther Nucleic Acids"},{"issue":"4","key":"736_CR53","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1093\/hmg\/ddp535","volume":"19","author":"G Douillard-Guilloux","year":"2010","unstructured":"Douillard-Guilloux G, Raben N, Takikita S, Ferry A, Vignaud A, Guillet-Deniau I, et al. Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. Hum Mol Genet. 2010;19(4):684\u201396.","journal-title":"Hum Mol Genet"},{"key":"736_CR54","doi-asserted-by":"crossref","unstructured":"\u2022 Tang B, Frasinyuk MS, Chikwana VM, Mahalingan KK, Morgan CA, Segvich DM, et al. Discovery and development of small-molecule inhibitors of glycogen synthase. J Med Chem. 2020;63(7):3538\u201351. This paper focuses on the development of new strategy of substrate reduction in Lysosomal Disorders, especially Pompe Disease. This paper mainly covers development of small-molecules that can inhibit Glycogen Synthetase. The implications are huge, as these treatments may be used not only as adjunctive therapy to existing enzyme replacement therapies in Lysosomal Disorders, but may potentially be used in at-risk asymptomatic individuals who carry mutations in genes responsible for Glycogen Storage disorders.","DOI":"10.1021\/acs.jmedchem.9b01851"}],"container-title":["Current Treatment Options in Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11940-022-00736-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11940-022-00736-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11940-022-00736-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T12:02:06Z","timestamp":1676289726000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11940-022-00736-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,4]]},"references-count":54,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["736"],"URL":"https:\/\/doi.org\/10.1007\/s11940-022-00736-1","relation":{},"ISSN":["1092-8480","1534-3138"],"issn-type":[{"value":"1092-8480","type":"print"},{"value":"1534-3138","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,4]]},"assertion":[{"value":"21 July 2022","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2022","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"Drs. Stevens and Milani declare that they have no financial interests. Dr. Mozaffar discloses an advisory role for and\/or receiving research funds from Alexion, Amicus, Argenx, Arvinas, Audentes, AvroBio, Horizon Therapeutics, Immunovant, Maze Therapeutics, Momenta (now Janssen), Sanofi-Genzyme, Sarepta, Spark Therapeutics, UCB, and Modis\/Zogenix. Dr. Mozaffar also serves on the data safety monitoring board for Acceleron, Avexis, and Sarepta.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}},{"value":"This article does not contain any studies with human or animal subjects performed by any of the authors.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights and Informed Consent"}}]}}