Toward Engineering the Mannose 6-Phosphate Elaboration Pathway in Plants for Enzyme Replacement Therapy of Lysosomal Storage Disorders
| Autor: | Tatyana Danyukova, Sandra Pohl, Allison R. Kermode, Ying Zeng, Xu He |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0106 biological sciences
congenital hereditary and neonatal diseases and abnormalities lysosomal enzyme Mucopolysaccharidosis Mannose Mannose 6-phosphate macromolecular substances Endocytosis 01 natural sciences Article mannose 6-phosphate (M6P) law.invention enzyme replacement therapy (ERT) 03 medical and health sciences chemistry.chemical_compound α-L-iduronidase (IDUA) law Lysosome Lysosomal storage disease medicine skin and connective tissue diseases transgenic plant 030304 developmental biology 0303 health sciences plant-based platform business.industry nutritional and metabolic diseases M6P elaboration machinery General Medicine Enzyme replacement therapy medicine.disease medicine.anatomical_structure chemistry Biochemistry nervous system Recombinant DNA business 010606 plant biology & botany |
| Zdroj: | Journal of Clinical Medicine Journal of Clinical Medicine; Volume 8; Issue 12; Pages: 2190 |
| ISSN: | 2077-0383 |
| Popis: | Mucopolysaccharidosis (MPS) I is a severe lysosomal storage disease caused by α-L-iduronidase (IDUA) deficiency, which results in accumulation of non-degraded glycosaminoglycans in lysosomes. Costly enzyme replacement therapy (ERT) is the conventional treatment for MPS I. Toward producing a more cost-effective and safe alternative to the commercial mammalian cell-based production systems, we have produced recombinant human IDUA in seeds of an Arabidopsis mutant to generate the enzyme in a biologically active and non-immunogenic form containing predominantly high mannose N-linked glycans. Recombinant enzyme in ERT is generally thought to require a mannose 6-phosphate (M6P) targeting signal for endocytosis into patient cells and for intracellular delivery to the lysosome. Toward effecting in planta phosphorylation, the human M6P elaboration machinery was successfully co-expressed along with the recombinant human IDUA using a single multi-gene construct. Uptake studies using purified putative M6P-IDUA generated in planta on cultured MPS I primary fibroblasts indicated that the endocytosed recombinant lysosomal enzyme led to substantial reduction of glycosaminoglycans. However, the efficiency of the putative M6P-IDUA in reducing glycosaminoglycan storage was comparable with the efficiency of the purified plant mannose-terminated IDUA, suggesting a poor in planta M6P-elaboration by the expressed machinery. Although the in planta M6P-tagging process efficiency would need to be improved, an exciting outcome of our work was that the plant-derived mannose-terminated IDUA yielded results comparable to those obtained with the commercial IDUA (Aldurazyme® (Sanofi, Paris, France)), and a significant amount of the plant-IDUA is trafficked by a M6P receptor-independent pathway. Thus, a plant-based platform for generating lysosomal hydrolases may represent an alternative and cost-effective strategy to the conventional ERT, without the requirement for additional processing to create the M6P motif. |
| Databáze: | OpenAIRE |
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