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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 ?-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.

SUBMITTER: Acosta W

PROVIDER: S-EPMC4585660 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies.

Acosta Walter W Ayala Jorge J Dolan Maureen C MC Cramer Carole L CL

Scientific reports 20150918

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 ...[more]

PMID: 26382970

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Project description:Mucopolysaccharidosis type I (MPS I) is a lysosomal disease resulting from deficiency in the ?-L-iduronidase (IDUA) hydrolase and subsequent accumulation of glycosaminoglycan (GAG). Clinically, enzyme replacement therapy (ERT) with IDUA achieves negligible neurological benefits presumably due to blood-brain-barrier (BBB) limitations. To investigate the plant lectin ricin B chain (RTB) as a novel carrier for enzyme delivery to the brain, an IDUA:RTB fusion protein (IDUAL), produced in N. benthamiana leaves, was tested in a murine model of Hurler syndrome (MPS I). Affect mice (n=3 for each group) were intravenously injected with a single dose of IDUAL (0.58, 2 or 5.8mgIDUAequivalents/kg) and analyzed after 24h. IDUA activities in liver, kidney and spleen increased significantly, and liver GAG levels were significantly reduced in all three groups. Plasma IDUA levels for all treated groups were high at 1h after injection and decreased by 95% at 4h, indicating efficient distribution into tissues. For long-term evaluations, IDUAL (0.58 or 2mg/kg, 8 weekly injections) was intravenously injected into MPS I mice (n=12 for each group). Thirteen days after the 8th injection, significant IDUA activity was detected in the liver and spleen. GAG levels in tissues including the brain cortex and cerebellum were significantly reduced in treated animals. Treated MPS I mice also showed significant improvement in neurocognitive testing. ELISA results showed that while there was a significant antibody response against IDUAL and plant-derived IDUA, there was no significant antibody response to RTB. No major toxicity or adverse events were observed. Together, these results showed that infusion of IDUAL allowed for significant IDUA levels and GAG reduction in the brain and subsequent neurological benefits. This RTB-mediated delivery may have significant implications for therapeutic protein delivery impacting a broad spectrum of lysosomal, and potentially neurological diseases.

Dataset Information

RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies.

Publications

RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies.

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