Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington’s disease phenotypes
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by striatal atrophy. Reduced trophic support due to decreased striatal levels of neurotrophins (NTs), mainly brain-derived neurotrophic factor (BDNF), contributes importantly to HD pathogenesis; restoring NTs...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050125000105 |
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| author | Danielle A. Simmons Sridhar Selvaraj Tingshuo Chen Gloria Cao Talita Souto Camelo Tyne L.M. McHugh Selena Gonzalez Renata M. Martin Juste Simanauskaite Nobuko Uchida Matthew H. Porteus Frank M. Longo |
| author_facet | Danielle A. Simmons Sridhar Selvaraj Tingshuo Chen Gloria Cao Talita Souto Camelo Tyne L.M. McHugh Selena Gonzalez Renata M. Martin Juste Simanauskaite Nobuko Uchida Matthew H. Porteus Frank M. Longo |
| author_sort | Danielle A. Simmons |
| collection | DOAJ |
| description | Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by striatal atrophy. Reduced trophic support due to decreased striatal levels of neurotrophins (NTs), mainly brain-derived neurotrophic factor (BDNF), contributes importantly to HD pathogenesis; restoring NTs has significant therapeutic potential. Human pluripotent stem cells (hPSCs) offer a scalable platform for NT delivery but have potential safety risks including teratoma formation. We engineered hPSCs to constitutively produce BDNF and contain inducible safeguards to eliminate these cells if safety concerns arise. This study examined the efficacy of intrastriatally transplanted striatal progenitor cells (STRpcs) derived from these hPSCs against HD phenotypes in R6/2 mice. Engrafted STRpcs overexpressing BDNF alleviated motor and cognitive deficits and reduced mutant huntingtin aggregates. Activating the inducible safety switch with rapamycin safely eliminated the engrafted cells. These results demonstrate that BDNF delivery via a novel hPSC-based platform incorporating safety switches could be a safe and effective HD therapeutic. |
| format | Article |
| id | doaj-art-c74c42d65e1d49be9179ded68061f51c |
| institution | Kabale University |
| issn | 2329-0501 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-c74c42d65e1d49be9179ded68061f51c2025-02-07T04:47:42ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012025-03-01331101415Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington’s disease phenotypesDanielle A. Simmons0Sridhar Selvaraj1Tingshuo Chen2Gloria Cao3Talita Souto Camelo4Tyne L.M. McHugh5Selena Gonzalez6Renata M. Martin7Juste Simanauskaite8Nobuko Uchida9Matthew H. Porteus10Frank M. Longo11Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Corresponding author: Danielle A. Simmons, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Wu Tsai Neuroscience Institute, Stanford University, Stanford, CA 94305, USAHuntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by striatal atrophy. Reduced trophic support due to decreased striatal levels of neurotrophins (NTs), mainly brain-derived neurotrophic factor (BDNF), contributes importantly to HD pathogenesis; restoring NTs has significant therapeutic potential. Human pluripotent stem cells (hPSCs) offer a scalable platform for NT delivery but have potential safety risks including teratoma formation. We engineered hPSCs to constitutively produce BDNF and contain inducible safeguards to eliminate these cells if safety concerns arise. This study examined the efficacy of intrastriatally transplanted striatal progenitor cells (STRpcs) derived from these hPSCs against HD phenotypes in R6/2 mice. Engrafted STRpcs overexpressing BDNF alleviated motor and cognitive deficits and reduced mutant huntingtin aggregates. Activating the inducible safety switch with rapamycin safely eliminated the engrafted cells. These results demonstrate that BDNF delivery via a novel hPSC-based platform incorporating safety switches could be a safe and effective HD therapeutic.http://www.sciencedirect.com/science/article/pii/S2329050125000105human pluripotent stem cellsneurotrophinHuntington’s diseasestriatal progenitorsbrain-derived neurotrophic factor |
| spellingShingle | Danielle A. Simmons Sridhar Selvaraj Tingshuo Chen Gloria Cao Talita Souto Camelo Tyne L.M. McHugh Selena Gonzalez Renata M. Martin Juste Simanauskaite Nobuko Uchida Matthew H. Porteus Frank M. Longo Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington’s disease phenotypes Molecular Therapy: Methods & Clinical Development human pluripotent stem cells neurotrophin Huntington’s disease striatal progenitors brain-derived neurotrophic factor |
| title | Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington’s disease phenotypes |
| title_full | Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington’s disease phenotypes |
| title_fullStr | Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington’s disease phenotypes |
| title_full_unstemmed | Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington’s disease phenotypes |
| title_short | Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington’s disease phenotypes |
| title_sort | human striatal progenitor cells that contain inducible safeguards and overexpress bdnf rescue huntington s disease phenotypes |
| topic | human pluripotent stem cells neurotrophin Huntington’s disease striatal progenitors brain-derived neurotrophic factor |
| url | http://www.sciencedirect.com/science/article/pii/S2329050125000105 |
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