TY - JOUR
T1 - RTB lectin-mediated delivery of lysosomal α-L-iduronidase mitigates disease manifestations systemically including the central nervous system
AU - Ou, Li
AU - Przybilla, Michael J.
AU - Koniar, Brenda
AU - Whitley, Chester B.
N1 - Publisher Copyright:
© 2017 The Authors
PY - 2018/2
Y1 - 2018/2
N2 - Mucopolysaccharidosis type I (MPS I) is a lysosomal disease resulting from deficiency in the α-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 5.8 mg IDUA equivalents/kg) and analyzed after 24 h. 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 1 h after injection and decreased by 95% at 4 h, indicating efficient distribution into tissues. For long-term evaluations, IDUAL (0.58 or 2 mg/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.
AB - Mucopolysaccharidosis type I (MPS I) is a lysosomal disease resulting from deficiency in the α-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 5.8 mg IDUA equivalents/kg) and analyzed after 24 h. 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 1 h after injection and decreased by 95% at 4 h, indicating efficient distribution into tissues. For long-term evaluations, IDUAL (0.58 or 2 mg/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.
KW - CNS protein delivery
KW - Enzyme replacement therapy
KW - Lysosomal disease
KW - RTB
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U2 - 10.1016/j.ymgme.2017.11.013
DO - 10.1016/j.ymgme.2017.11.013
M3 - Article
C2 - 29198892
AN - SCOPUS:85035334874
SN - 1096-7192
VL - 123
SP - 105
EP - 111
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 2
ER -