2. Academic Validation
  3. Therapeutic delivery of recombinant glucocerebrosidase enzyme-containing extracellular vesicles to human cells from Gaucher disease patients

Therapeutic delivery of recombinant glucocerebrosidase enzyme-containing extracellular vesicles to human cells from Gaucher disease patients

  • Orphanet J Rare Dis. 2024 Oct 2;19(1):363. doi: 10.1186/s13023-024-03376-7.
Keatdamrong Janpipatkul # 1,  Nareerat Sutjarit # 2,  Amornrat Tangprasittipap 3,  Tai Chaiamarit 4,  Pawarit Innachai 3,  Kanoknetr Suksen 4,  Tanida Chokpanuwat 4,  Thipwimol Tim-Aroon 5,  Usanarat Anurathapan 5,  Natee Jearawiriyapaisarn 6,  Alisa Tubsuwan 6,  Supareak Bowornpinyo 7 8,  Nithi Asavapanumas 9,  Arthit Chairoungdua 4 8,  Kanit Bhukhai 10,  Suradej Hongeng 5 8
Affiliations

Affiliations

  • 1 Department of Basic Medical Science, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand.
  • 2 Graduate Program in Nutrition, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
  • 3 Office of Research, Academic Affairs and Innovations, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
  • 4 Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 5 Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Ratchathewi, Thailand.
  • 6 Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand.
  • 7 Department of Biotechnology, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 8 Excellent Center for Drug Discovery, Mahidol University, Bangkok, Thailand.
  • 9 Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Pla, Bang Phli, Samut Prakan, Thailand.
  • 10 Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand. kanit.bhu@mahidol.ac.th.
  • # Contributed equally.
PMID: 39358794 DOI: 10.1186/s13023-024-03376-7
Abstract

Background: Gaucher disease (GD) is one of the most common types of lysosomal storage diseases (LSDs) caused by pathogenic variants of lysosomal β-glucocerebrosidase gene (GBA1), resulting in the impairment of Glucocerebrosidase (GCase) Enzyme function and the accumulation of a glycolipid substrate, glucosylceramide (GlcCer) within lysosomes. Current therapeutic approaches such as Enzyme replacement therapy and substrate reduction therapy cannot fully rescue GD pathologies, especially neurological symptoms. Meanwhile, delivery of lysosomal Enzymes to the endocytic compartment of affected human cells is a promising strategy for treating neuropathic LSDs.

Result: Here, we describe a novel approach to restore GCase Enzyme in cells from neuropathic GD patients by producing extracellular vesicle (EVs)-containing GCase from cells overexpressing GBA1 gene. Lentiviral vectors containing modified GBA1 were introduced into HEK293T cells to produce a stable cell line that provides a sustainable source of functional GCase Enzyme. The GBA1-overexpressing cells released EV-containing GCase Enzyme, that is capable of entering into and localizing in the endocytic compartment of recipient cells, including THP-1 macrophage, SH-SY5Y neuroblastoma, and macrophages and neurons derived from induced pluripotent stem cells (iPSCs) of neuropathic GD patients. Importantly, the recipient cells exhibit higher GCase Enzyme activity.

Conclusion: This study presents a promising therapeutic strategy to treat severe types of LSDs. It involves delivering lysosomal Enzymes to the endocytic compartment of human cells affected by conditions such as GDs with neurological symptoms, as well as potentially Other neurological disorders impacting lysosomes.

Keywords

Extracellular vesicles; Gaucher disease; Glucocerebrosidase; HEK293T cell; Lentiviral vector; Macrophages; Neurons.

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