title: RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies.
abstract: Enzyme replacement therapies have revolutionized patient treatment for multiple rare lysosomal storage diseases but show limited effectiveness for addressing pathologies in "hard-to-treat" organs and tissues including brain and bone. Here we investigate the plant lectin RTB as a novel carrier for human lysosomal enzymes. RTB enters mammalian cells by multiple mechanisms including both adsorptive-mediated and receptor-mediated endocytosis, and thus provides access to a broader array of organs and cells. Fusion proteins comprised of RTB and human α-L-iduronidase, the corrective enzyme for Mucopolysaccharidosis type I, were produced using a tobacco-based expression system. Fusion products retained both lectin selectivity and enzyme activity, were efficiently endocytosed into human fibroblasts, and corrected the disease phenotype of mucopolysaccharidosis patient fibroblasts in vitro. RTB-mediated delivery was independent of high-mannose and mannose-6-phosphate receptors, which are exploited for delivery of currently approved lysosomal enzyme therapeutics. Thus, the RTB carrier may support distinct in vivo pharmacodynamics with potential to address hard-to-treat tissues.
authors.affiliation: Arkansas Biosciences Institute at Arkansas State University-Jonesboro, State University, Arkansas, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Acosta
authors.affiliation: Arkansas Biosciences Institute at Arkansas State University-Jonesboro, State University, Arkansas, USA.|BioStrategies LC, State University, Arkansas, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ayala
authors.affiliation: Arkansas Biosciences Institute at Arkansas State University-Jonesboro, State University, Arkansas, USA.|Department of Biological Sciences, Arkansas State University-Jonesboro, State University, Arkansas, USA.
authors.forename: Maureen C
authors.initials: MC
authors.lastname: Dolan
authors.affiliation: Arkansas Biosciences Institute at Arkansas State University-Jonesboro, State University, Arkansas, USA.|Department of Biological Sciences, Arkansas State University-Jonesboro, State University, Arkansas, USA.|BioStrategies LC, State University, Arkansas, USA.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Cramer
mesh_terms: D004337:Drug Carriers; D016503:Drug Delivery Systems; D056947:Enzyme Replacement Therapy; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007068:Iduronidase / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D016464:Lysosomal Storage Diseases / Q000628:therapy; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D010641:Phenotype; D018515:Plant Leaves / Q000235:genetics / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D012276:Ricin / Q000235:genetics / Q000378:metabolism; D014026:Nicotiana / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D006025:Glycosaminoglycans; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D012276:Ricin; D007068:Iduronidase