An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model
Abstract Hematopoietic stem and progenitor cells (HSPCs) can establish a long‐lasting microglia‐like progeny in the central nervous system of properly myeloablated hosts. We exploited this approach to treat the severe CLN1 neurodegenerative disorder, which is the most aggressive form of neuronal cer...
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202215968 |
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| author | Marco Peviani Sabyasachi Das Janki Patel Odella Jno‐Charles Rajesh Kumar Ana Zguro Tyler D Mathews Paolo Cabras Rita Milazzo Eleonora Cavalca Valentina Poletti Alessandra Biffi |
| author_facet | Marco Peviani Sabyasachi Das Janki Patel Odella Jno‐Charles Rajesh Kumar Ana Zguro Tyler D Mathews Paolo Cabras Rita Milazzo Eleonora Cavalca Valentina Poletti Alessandra Biffi |
| author_sort | Marco Peviani |
| collection | DOAJ |
| description | Abstract Hematopoietic stem and progenitor cells (HSPCs) can establish a long‐lasting microglia‐like progeny in the central nervous system of properly myeloablated hosts. We exploited this approach to treat the severe CLN1 neurodegenerative disorder, which is the most aggressive form of neuronal ceroid lipofuscinoses due to palmitoyl‐protein thioesterase‐1 (PPT1) deficiency. We here provide the first evidence that (i) transplantation of wild‐type HSPCs exerts partial but long‐lasting mitigation of CLN1 symptoms; (ii) transplantation of HSPCs over‐expressing hPPT1 by lentiviral gene transfer enhances the therapeutic benefit of HSPCs transplant, with first demonstration of such a dose–effect benefit for a purely neurodegenerative condition like CLN1 disease; (iii) transplantation of hPPT1 over‐expressing HSPCs by a novel intracerebroventricular (ICV) approach is sufficient to transiently ameliorate CLN1‐symptoms in the absence of hematopoietic tissue engraftment of the transduced cells; and (iv) combinatorial transplantation of transduced HSPCs intravenously and ICV results in a robust therapeutic benefit, particularly on symptomatic animals. Overall, these findings provide first evidence of efficacy and feasibility of this novel approach to treat CLN1 disease and possibly other neurodegenerative conditions, paving the way for its future clinical application. |
| format | Article |
| id | doaj-art-08b15516f1d54eaaa6b3d844eea63aa5 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-08b15516f1d54eaaa6b3d844eea63aa52024-11-10T12:37:18ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-03-0115412010.15252/emmm.202215968An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse modelMarco Peviani0Sabyasachi Das1Janki Patel2Odella Jno‐Charles3Rajesh Kumar4Ana Zguro5Tyler D Mathews6Paolo Cabras7Rita Milazzo8Eleonora Cavalca9Valentina Poletti10Alessandra Biffi11Gene Therapy Program, Dana‐Farber/Boston Children's Cancer and Blood Disorders CenterGene Therapy Program, Dana‐Farber/Boston Children's Cancer and Blood Disorders CenterGene Therapy Program, Dana‐Farber/Boston Children's Cancer and Blood Disorders CenterGene Therapy Program, Dana‐Farber/Boston Children's Cancer and Blood Disorders CenterGene Therapy Program, Dana‐Farber/Boston Children's Cancer and Blood Disorders CenterGene Therapy Program, Dana‐Farber/Boston Children's Cancer and Blood Disorders CenterGene Therapy Program, Dana‐Farber/Boston Children's Cancer and Blood Disorders CenterDepartment of Biology and Biotechnology “L. Spallanzani”, University of PaviaSan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET), San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET), San Raffaele Scientific InstituteGene Therapy Program, Dana‐Farber/Boston Children's Cancer and Blood Disorders CenterGene Therapy Program, Dana‐Farber/Boston Children's Cancer and Blood Disorders CenterAbstract Hematopoietic stem and progenitor cells (HSPCs) can establish a long‐lasting microglia‐like progeny in the central nervous system of properly myeloablated hosts. We exploited this approach to treat the severe CLN1 neurodegenerative disorder, which is the most aggressive form of neuronal ceroid lipofuscinoses due to palmitoyl‐protein thioesterase‐1 (PPT1) deficiency. We here provide the first evidence that (i) transplantation of wild‐type HSPCs exerts partial but long‐lasting mitigation of CLN1 symptoms; (ii) transplantation of HSPCs over‐expressing hPPT1 by lentiviral gene transfer enhances the therapeutic benefit of HSPCs transplant, with first demonstration of such a dose–effect benefit for a purely neurodegenerative condition like CLN1 disease; (iii) transplantation of hPPT1 over‐expressing HSPCs by a novel intracerebroventricular (ICV) approach is sufficient to transiently ameliorate CLN1‐symptoms in the absence of hematopoietic tissue engraftment of the transduced cells; and (iv) combinatorial transplantation of transduced HSPCs intravenously and ICV results in a robust therapeutic benefit, particularly on symptomatic animals. Overall, these findings provide first evidence of efficacy and feasibility of this novel approach to treat CLN1 disease and possibly other neurodegenerative conditions, paving the way for its future clinical application.https://doi.org/10.15252/emmm.202215968CLN1hematopoietic stem cell gene therapylysosomal storage disordermicroglia |
| spellingShingle | Marco Peviani Sabyasachi Das Janki Patel Odella Jno‐Charles Rajesh Kumar Ana Zguro Tyler D Mathews Paolo Cabras Rita Milazzo Eleonora Cavalca Valentina Poletti Alessandra Biffi An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model EMBO Molecular Medicine CLN1 hematopoietic stem cell gene therapy lysosomal storage disorder microglia |
| title | An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model |
| title_full | An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model |
| title_fullStr | An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model |
| title_full_unstemmed | An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model |
| title_short | An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model |
| title_sort | innovative hematopoietic stem cell gene therapy approach benefits cln1 disease in the mouse model |
| topic | CLN1 hematopoietic stem cell gene therapy lysosomal storage disorder microglia |
| url | https://doi.org/10.15252/emmm.202215968 |
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