{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T18:58:05Z","timestamp":1770749885634,"version":"3.50.0"},"reference-count":54,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T00:00:00Z","timestamp":1660867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R44NS084565"],"award-info":[{"award-number":["R44NS084565"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>GM1-gangliosidosis is a catastrophic, neurodegenerative lysosomal storage disease caused by a deficiency of lysosomal \u03b2-galactosidase (\u03b2-Gal). The primary substrate of the enzyme is GM1-ganglioside (GM1), a sialylated glycosphingolipid abundant in nervous tissue. Patients with GM1-gangliosidosis present with massive and progressive accumulation of GM1 in the central nervous system (CNS), which leads to mental and motor decline, progressive neurodegeneration, and early death. No therapy is currently available for this lysosomal storage disease. Here, we describe a proof-of-concept preclinical study toward the development of enzyme replacement therapy (ERT) for GM1-gangliosidosis using a recombinant murine \u03b2-Gal fused to the plant lectin subunit B of ricin (m\u03b2-Gal:RTB). We show that long-term, bi-weekly systemic injection of m\u03b2-Gal:RTB in the \u03b2-Gal\u2212\/\u2212 mouse model resulted in widespread internalization of the enzyme by cells of visceral organs, with consequent restoration of enzyme activity. Most importantly, \u03b2-Gal activity was detected in several brain regions. This was accompanied by a reduction of accumulated GM1, reversal of neuroinflammation, and decrease in the apoptotic marker caspase 3. These results indicate that the RTB lectin delivery module enhances both the CNS-biodistribution pattern and the therapeutic efficacy of the \u03b2-Gal ERT, with the potential to translate to a clinical setting for the treatment of GM1-gangliosidosis.<\/jats:p>","DOI":"10.3390\/cells11162579","type":"journal-article","created":{"date-parts":[[2022,8,21]],"date-time":"2022-08-21T21:05:51Z","timestamp":1661115951000},"page":"2579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Preclinical Enzyme Replacement Therapy with a Recombinant \u03b2-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-Gangliosidosis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0630-1715","authenticated-orcid":false,"given":"Jason Andrew","family":"Weesner","sequence":"first","affiliation":[{"name":"Department of Genetics, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"},{"name":"Department of Anatomy and Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ida","family":"Annunziata","sequence":"additional","affiliation":[{"name":"Department of Genetics, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"},{"name":"Compliance Office, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianhong","family":"Yang","sequence":"additional","affiliation":[{"name":"BioStrategies, LC, P.O. Box 2428, State University, Jonesboro, AR 72467, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5525-306X","authenticated-orcid":false,"given":"Walter","family":"Acosta","sequence":"additional","affiliation":[{"name":"BioStrategies, LC, P.O. Box 2428, State University, Jonesboro, AR 72467, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elida","family":"Gomero","sequence":"additional","affiliation":[{"name":"Department of Genetics, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2107-5389","authenticated-orcid":false,"given":"Huimin","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Genetics, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7498-1292","authenticated-orcid":false,"given":"Diantha","family":"van de Vlekkert","sequence":"additional","affiliation":[{"name":"Department of Genetics, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Ayala","sequence":"additional","affiliation":[{"name":"BioStrategies, LC, P.O. Box 2428, State University, Jonesboro, AR 72467, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohui","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Genetics, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leigh Ellen","family":"Fremuth","sequence":"additional","affiliation":[{"name":"Department of Genetics, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David N.","family":"Radin","sequence":"additional","affiliation":[{"name":"BioStrategies, LC, P.O. Box 2428, State University, Jonesboro, AR 72467, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carole L.","family":"Cramer","sequence":"additional","affiliation":[{"name":"BioStrategies, LC, P.O. Box 2428, State University, Jonesboro, AR 72467, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1747-7502","authenticated-orcid":false,"given":"Alessandra","family":"d\u2019Azzo","sequence":"additional","affiliation":[{"name":"Department of Genetics, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"},{"name":"Department of Anatomy and Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41572-018-0025-4","article-title":"Lysosomal storage diseases","volume":"4","author":"Platt","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4937","DOI":"10.1016\/S0021-9258(19)85585-0","article-title":"Biosynthesis of lysosomal enzymes in fibroblasts. Synthesis as precursors of higher molecular weight","volume":"255","author":"Hasilik","year":"1980","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1083\/jcb.104.6.1743","article-title":"Lysosomal enzyme precursors in coated vesicles derived from the exocytic and endocytic pathways","volume":"104","author":"Lemansky","year":"1987","journal-title":"J. Cell. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Trivedi, P.C., Bartlett, J.J., and Pulinilkunnil, T. (2020). Lysosomal Biology and Function: Modern View of Cellular Debris Bin. Cells, 9.","DOI":"10.3390\/cells9051131"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3846","DOI":"10.1016\/S0021-9258(17)41937-5","article-title":"Intermolecular association of lysosomal protein precursors during biosynthesis","volume":"269","author":"Zhu","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_6","first-page":"157","article-title":"Recent advances in gene therapy for lysosomal storage disorders","volume":"8","author":"Rastall","year":"2015","journal-title":"Appl. Clin. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.omtm.2020.11.012","article-title":"Galactosialidosis: Preclinical enzyme replacement therapy in a mouse model of the disease, a proof of concept","volume":"20","author":"Cadaoas","year":"2021","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"624988","DOI":"10.3389\/fmolb.2021.624988","article-title":"Clinical Trials for Gene Therapy in Lysosomal Diseases With CNS Involvement","volume":"8","author":"Sevin","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1186\/s13052-018-0562-1","article-title":"Enzyme replacement therapy: Efficacy and limitations","volume":"44","author":"Concolino","year":"2018","journal-title":"Ital. J. Pediatr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"559804","DOI":"10.3389\/fmolb.2020.559804","article-title":"CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges","volume":"7","author":"Edelmann","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13532","DOI":"10.1074\/jbc.RA119.009811","article-title":"Intracerebroventricular enzyme replacement therapy with \u03b2-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice","volume":"295","author":"Chen","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2928","DOI":"10.1021\/mp500258p","article-title":"Insulin receptor antibody-sulfamidase fusion protein penetrates the primate blood-brain barrier and reduces glycosoaminoglycans in Sanfilippo type A cells","volume":"11","author":"Boado","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100748","DOI":"10.1016\/j.ymgmr.2021.100748","article-title":"Examination of a blood-brain barrier targeting \u03b2-galactosidase-monoclonal antibody fusion protein in a murine model of GM1-gangliosidosis","volume":"27","author":"Przybilla","year":"2021","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1016\/j.ymthe.2018.02.032","article-title":"A Blood-Brain-Barrier-Penetrating Anti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic Mucopolysaccharidosis II","volume":"26","author":"Sonoda","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ymgme.2017.11.013","article-title":"RTB lectin-mediated delivery of lysosomal \u03b1-l-iduronidase mitigates disease manifestations systemically including the central nervous system","volume":"123","author":"Ou","year":"2018","journal-title":"Mol. Genet. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.ymgme.2015.12.002","article-title":"Enzyme replacement for GM1-gangliosidosis: Uptake, lysosomal activation, and cellular disease correction using a novel \u03b2-galactosidase:RTB lectin fusion","volume":"117","author":"Condori","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Acosta, W., and Cramer, C.L. (2020). Targeting Macromolecules to CNS and Other Hard-to-Treat Organs Using Lectin-Mediated Delivery. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030971"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"734878","DOI":"10.3389\/fgene.2021.734878","article-title":"GM1 Gangliosidosis-A Mini-Review","volume":"12","author":"Nicoli","year":"2021","journal-title":"Front. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"209","DOI":"10.2147\/TACG.S206076","article-title":"GM1 Gangliosidosis: Mechanisms and Management","volume":"14","author":"Rha","year":"2021","journal-title":"Appl. Clin. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1007\/s00018-013-1538-3","article-title":"Lysosomal multienzyme complex: Pros and cons of working together","volume":"71","author":"Bonten","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"28430","DOI":"10.1074\/jbc.M109.031419","article-title":"Heterodimerization of the sialidase NEU1 with the chaperone protective protein\/cathepsin A prevents its premature oligomerization","volume":"284","author":"Bonten","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.1101\/gad.9.21.2623","article-title":"Mouse model for the lysosomal disorder galactosialidosis and correction of the phenotype with overexpressing erythroid precursor cells","volume":"9","author":"Zhou","year":"1995","journal-title":"Genes Dev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.ymgme.2011.09.016","article-title":"Murine \u03b2-galactosidase stability is not dependent on temperature or protective protein\/cathepsin A","volume":"104","author":"Lambourne","year":"2011","journal-title":"Mol. Genet. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Eikelberg, D., Lehmbecker, A., Brogden, G., Tongtako, W., Hahn, K., Habierski, A., Hennermann, J.B., Naim, H.Y., Felmy, F., and Baumg\u00e4rtner, W. (2020). Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human G(M1)-Gangliosidosis. J. Clin. Med., 9.","DOI":"10.3390\/jcm9041004"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1093\/hmg\/6.2.205","article-title":"Generalized CNS disease and massive GM1-ganglioside accumulation in mice defective in lysosomal acid beta-galactosidase","volume":"6","author":"Hahn","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1177\/1535370221993052","article-title":"A GM1 gangliosidosis mutant mouse model exhibits activated microglia and disturbed autophagy","volume":"246","author":"Liu","year":"2021","journal-title":"Exp. Biol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1023\/A:1018573518127","article-title":"Beta-galactosidase-deficient mouse as an animal model for GM1-gangliosidosis","volume":"14","author":"Matsuda","year":"1997","journal-title":"Glycoconj. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.ymgme.2018.11.002","article-title":"Comprehensive behavioral and biochemical outcomes of novel murine models of GM1-gangliosidosis and Morquio syndrome type B","volume":"126","author":"Przybilla","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1093\/brain\/awg089","article-title":"Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis","volume":"126","author":"Jeyakumar","year":"2003","journal-title":"Brain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.molcel.2009.10.021","article-title":"GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis","volume":"36","author":"Sano","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1182\/blood-2005-03-1189","article-title":"Chemokine-induced recruitment of genetically modified bone marrow cells into the CNS of GM1-gangliosidosis mice corrects neuronal pathology","volume":"106","author":"Sano","year":"2005","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.molcel.2004.08.029","article-title":"GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis","volume":"15","author":"Tessitore","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Baek, R.C., Broekman, M.L., Leroy, S.G., Tierney, L.A., Sandberg, M.A., d\u2019Azzo, A., Seyfried, T.N., and Sena-Esteves, M. (2010). AAV-mediated gene delivery in adult GM1-gangliosidosis mice corrects lysosomal storage in CNS and improves survival. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013468"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"352","DOI":"10.2174\/1566523222666220304092732","article-title":"AAV9-coGLB1 Improves Lysosomal Storage and Rescues Central Nervous System Inflammation in a Mutant Mouse Model of GM1 Gangliosidosis","volume":"22","author":"Liu","year":"2022","journal-title":"Curr. Gene Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.omtm.2022.04.012","article-title":"Hematopoietic stem cell gene therapy ameliorates CNS involvement in murine model of GM1-gangliosidosis","volume":"25","author":"Tsunogai","year":"2022","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/978-1-59745-407-0_4","article-title":"Rapid system for evaluating bioproduction capacity of complex pharmaceutical proteins in plants","volume":"483","author":"Medrano","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1203\/01.PDR.0000113789.30640.5C","article-title":"Monitoring dose response of enzyme replacement therapy in feline mucopolysaccharidosis type VI by tandem mass spectrometry","volume":"55","author":"Crawley","year":"2004","journal-title":"Pediatr. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"20655","DOI":"10.1016\/S0021-9258(19)47114-7","article-title":"Alternative splicing of beta-galactosidase mRNA generates the classic lysosomal enzyme and a beta-galactosidase-related protein","volume":"264","author":"Morreau","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/humu.1380030205","article-title":"Insertion of a T next to the donor splice site of intron 1 causes aberrantly spliced mRNA in a case of infantile GM1-gangliosidosis","volume":"3","author":"Morrone","year":"1994","journal-title":"Hum. Mutat."},{"key":"ref_40","unstructured":"Radin, D.N., and Acosta, W. (2019). Materials and Methods for Mitigating Immune-Sensitization. (US20190046637A1), U.S. Patent."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/sj.cdd.4400476","article-title":"Emerging roles of caspase-3 in apoptosis","volume":"6","author":"Porter","year":"1999","journal-title":"Cell Death Differ."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.ymgme.2008.02.005","article-title":"Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis","volume":"94","author":"Speak","year":"2008","journal-title":"Mol. Genet. Metab."},{"key":"ref_43","unstructured":"Tifft, C.J. (2022, July 01). A Phase 1\/2 Study of Intravenous Gene Transfer With an AAV9 Vector Expressing Human Beta-Galactosidase in Type I and Type II GM1 Gangliosidosis, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03952637."},{"key":"ref_44","first-page":"82","article-title":"Management of Gaucher disease: Enzyme replacement therapy","volume":"12","author":"Zimran","year":"2014","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/ajmg.c.31321","article-title":"Infantile Pompe disease on ERT: Update on clinical presentation, musculoskeletal management, and exercise considerations","volume":"160c","author":"Case","year":"2012","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ceccarini, M.R., Codini, M., Conte, C., Patria, F., Cataldi, S., Bertelli, M., Albi, E., and Beccari, T. (2018). Alpha-Mannosidosis: Therapeutic Strategies. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051500"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1590\/S1415-47572014000100006","article-title":"Enzyme replacement therapy for Mucopolysaccharidosis Type I among patients followed within the MPS Brazil Network","volume":"37","author":"Dornelles","year":"2014","journal-title":"Genet. Mol. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.ymgme.2014.10.017","article-title":"First human treatment with investigational rhGUS enzyme replacement therapy in an advanced stage MPS VII patient","volume":"114","author":"Fox","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13023-016-0414-2","article-title":"Moving towards effective therapeutic strategies for Neuronal Ceroid Lipofuscinosis","volume":"11","author":"Geraets","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s10545-014-9686-7","article-title":"Long-term experience with enzyme replacement therapy (ERT) in MPS II patients with a severe phenotype: An international case series","volume":"37","author":"Lampe","year":"2014","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.ymgme.2016.02.003","article-title":"Cardiac structure and function and effects of enzyme replacement therapy in patients with mucopolysaccharidoses I, II, IVA and VI","volume":"117","author":"Lin","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"591","DOI":"10.2147\/DDDT.S149264","article-title":"Lysosomal Acid Lipase Deficiency: Therapeutic Options","volume":"14","author":"Pastores","year":"2020","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ymgme.2018.04.007","article-title":"The effect of enzyme replacement therapy on clinical outcomes in paediatric patients with Fabry disease\u2014A systematic literature review by a European panel of experts","volume":"126","author":"Spada","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1517\/21678707.2015.1086640","article-title":"Enzyme replacement therapy for treating mucopolysaccharidosis type IVA (Morquio A syndrome): Effect and limitations","volume":"3","author":"Tomatsu","year":"2015","journal-title":"Expert Opin Orphan Drugs"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/16\/2579\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:12:25Z","timestamp":1760141545000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/16\/2579"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,19]]},"references-count":54,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["cells11162579"],"URL":"https:\/\/doi.org\/10.3390\/cells11162579","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,19]]}}}