iPSC-derived neural precursor cells engineering GBA1 recovers acid β-glucosidase deficiency and diminishes α-synuclein and neuropathology
Mutations in GBA1, encoding the lysosomal acid β-glucosidase (GCase), cause neuronopathic Gaucher disease (nGD) and promote Parkinson disease (PD). The mutations on GBA1 include deletion and missense mutations that are pathological and lead to GCase deficiency in Gaucher disease. Both nGD and PD lac...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050123000438 |
| _version_ | 1797807172171595776 |
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| author | Yanyan Peng Benjamin Liou Yi Lin Christopher N. Mayhew Sheila M. Fleming Ying Sun |
| author_facet | Yanyan Peng Benjamin Liou Yi Lin Christopher N. Mayhew Sheila M. Fleming Ying Sun |
| author_sort | Yanyan Peng |
| collection | DOAJ |
| description | Mutations in GBA1, encoding the lysosomal acid β-glucosidase (GCase), cause neuronopathic Gaucher disease (nGD) and promote Parkinson disease (PD). The mutations on GBA1 include deletion and missense mutations that are pathological and lead to GCase deficiency in Gaucher disease. Both nGD and PD lack disease-modifying treatments and are critical unmet medical needs. In this study, we evaluated a cell therapy treatment using mouse iPSC-derived neural precursor cells (NPCs) engineered to overexpress GCase (termed hGBA1-NPCs). The hGBA1-NPCs secreted GCase that was taken up by adjacent mouse Gba−/− neurons and improved GCase activity, reduced GCase substrate accumulation, and improved mitochondrial function. Short-term in vivo effects were evaluated in 9H/PS-NA mice, an nGD mouse model exhibiting neuropathology and α-synuclein aggregation, the typical PD phenotypes. Intravenously administrated hGBA1-NPCs were engrafted throughout the brain and differentiated into neural lineages. GCase activity was increased in various brain regions of treated 9H/PS-NA mice. Compared with vehicle, hGBA1-NPC-transplanted mice showed ∼50% reduction of α-synuclein aggregates in the substantia nigra, significant reduction of neuroinflammation and neurodegeneration in the regions of NPC migration, and increased expression of neurotrophic factors that support neural cell function. Together, these results support the therapeutic benefit of intravenous delivery of iPSC-derived NPCs overexpressing GCase in mitigating nGD and PD phenotypes and establish the feasibility of combined cell and gene therapy for GBA1-associated PD. |
| first_indexed | 2024-03-13T06:18:34Z |
| format | Article |
| id | doaj.art-52aaf75278eb4cae9ea6f54af7a3ab3d |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-03-13T06:18:34Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-52aaf75278eb4cae9ea6f54af7a3ab3d2023-06-10T04:27:44ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012023-06-0129185201iPSC-derived neural precursor cells engineering GBA1 recovers acid β-glucosidase deficiency and diminishes α-synuclein and neuropathologyYanyan Peng0Benjamin Liou1Yi Lin2Christopher N. Mayhew3Sheila M. Fleming4Ying Sun5Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USADivision of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USADivision of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USADivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USACollege of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USADivision of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Corresponding author: Ying Sun, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.Mutations in GBA1, encoding the lysosomal acid β-glucosidase (GCase), cause neuronopathic Gaucher disease (nGD) and promote Parkinson disease (PD). The mutations on GBA1 include deletion and missense mutations that are pathological and lead to GCase deficiency in Gaucher disease. Both nGD and PD lack disease-modifying treatments and are critical unmet medical needs. In this study, we evaluated a cell therapy treatment using mouse iPSC-derived neural precursor cells (NPCs) engineered to overexpress GCase (termed hGBA1-NPCs). The hGBA1-NPCs secreted GCase that was taken up by adjacent mouse Gba−/− neurons and improved GCase activity, reduced GCase substrate accumulation, and improved mitochondrial function. Short-term in vivo effects were evaluated in 9H/PS-NA mice, an nGD mouse model exhibiting neuropathology and α-synuclein aggregation, the typical PD phenotypes. Intravenously administrated hGBA1-NPCs were engrafted throughout the brain and differentiated into neural lineages. GCase activity was increased in various brain regions of treated 9H/PS-NA mice. Compared with vehicle, hGBA1-NPC-transplanted mice showed ∼50% reduction of α-synuclein aggregates in the substantia nigra, significant reduction of neuroinflammation and neurodegeneration in the regions of NPC migration, and increased expression of neurotrophic factors that support neural cell function. Together, these results support the therapeutic benefit of intravenous delivery of iPSC-derived NPCs overexpressing GCase in mitigating nGD and PD phenotypes and establish the feasibility of combined cell and gene therapy for GBA1-associated PD.http://www.sciencedirect.com/science/article/pii/S2329050123000438cell therapyneuronopathic Gaucher diseaseParkinson diseaseneurodegenerationneural precursor cellacid β-glucosidase |
| spellingShingle | Yanyan Peng Benjamin Liou Yi Lin Christopher N. Mayhew Sheila M. Fleming Ying Sun iPSC-derived neural precursor cells engineering GBA1 recovers acid β-glucosidase deficiency and diminishes α-synuclein and neuropathology Molecular Therapy: Methods & Clinical Development cell therapy neuronopathic Gaucher disease Parkinson disease neurodegeneration neural precursor cell acid β-glucosidase |
| title | iPSC-derived neural precursor cells engineering GBA1 recovers acid β-glucosidase deficiency and diminishes α-synuclein and neuropathology |
| title_full | iPSC-derived neural precursor cells engineering GBA1 recovers acid β-glucosidase deficiency and diminishes α-synuclein and neuropathology |
| title_fullStr | iPSC-derived neural precursor cells engineering GBA1 recovers acid β-glucosidase deficiency and diminishes α-synuclein and neuropathology |
| title_full_unstemmed | iPSC-derived neural precursor cells engineering GBA1 recovers acid β-glucosidase deficiency and diminishes α-synuclein and neuropathology |
| title_short | iPSC-derived neural precursor cells engineering GBA1 recovers acid β-glucosidase deficiency and diminishes α-synuclein and neuropathology |
| title_sort | ipsc derived neural precursor cells engineering gba1 recovers acid β glucosidase deficiency and diminishes α synuclein and neuropathology |
| topic | cell therapy neuronopathic Gaucher disease Parkinson disease neurodegeneration neural precursor cell acid β-glucosidase |
| url | http://www.sciencedirect.com/science/article/pii/S2329050123000438 |
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