RTB lectin-mediated delivery of lysosomal α-L-iduronidase mitigates disease manifestations systemically including the central nervous system

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)105-111
Number of pages7
JournalMolecular Genetics and Metabolism
Volume123
Issue number2
DOIs
StatePublished - Feb 2018

Bibliographical note

Funding Information:
The investigators thank BioStrategies LC (State University, AR) for IDUAL protein and funding under an NIH SBIR grant R43NS086326 . Dr. Li Ou is a fellow of the Lysosomal Disease Network ( U54NS065768 ). The Lysosomal Disease Network is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS. This consortium is funded through a collaboration between NCATS, the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Funding Information:
The investigators thank BioStrategies LC (State University, AR) for IDUAL protein and funding under an NIH SBIR grant R43NS086326. Dr. Li Ou is a fellow of the Lysosomal Disease Network (U54NS065768). The Lysosomal Disease Network is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS. This consortium is funded through a collaboration between NCATS, the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Keywords

  • CNS protein delivery
  • Enzyme replacement therapy
  • Lysosomal disease
  • RTB

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