Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe‐affected non‐human primates by intracerebral lentiviral gene therapy
Abstract Metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD or Krabbe disease) are severe neurodegenerative lysosomal storage diseases (LSD) caused by arylsulfatase A (ARSA) and galactosylceramidase (GALC) deficiency, respectively. Our previous studies established lentiviral gen...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2016-03-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201505850 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849342014959648768 |
|---|---|
| author | Vasco Meneghini Annalisa Lattanzi Luigi Tiradani Gabriele Bravo Francesco Morena Francesca Sanvito Andrea Calabria John Bringas Jeanne M Fisher‐Perkins Jason P Dufour Kate C Baker Claudio Doglioni Eugenio Montini Bruce A Bunnell Krystof Bankiewicz Sabata Martino Luigi Naldini Angela Gritti |
| author_facet | Vasco Meneghini Annalisa Lattanzi Luigi Tiradani Gabriele Bravo Francesco Morena Francesca Sanvito Andrea Calabria John Bringas Jeanne M Fisher‐Perkins Jason P Dufour Kate C Baker Claudio Doglioni Eugenio Montini Bruce A Bunnell Krystof Bankiewicz Sabata Martino Luigi Naldini Angela Gritti |
| author_sort | Vasco Meneghini |
| collection | DOAJ |
| description | Abstract Metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD or Krabbe disease) are severe neurodegenerative lysosomal storage diseases (LSD) caused by arylsulfatase A (ARSA) and galactosylceramidase (GALC) deficiency, respectively. Our previous studies established lentiviral gene therapy (GT) as a rapid and effective intervention to provide pervasive supply of therapeutic lysosomal enzymes in CNS tissues of MLD and GLD mice. Here, we investigated whether this strategy is similarly effective in juvenile non‐human primates (NHP). To provide proof of principle for tolerability and biological efficacy of the strategy, we established a comprehensive study in normal NHP delivering a clinically relevant lentiviral vector encoding for the human ARSA transgene. Then, we injected a lentiviral vector coding for the human GALC transgene in Krabbe‐affected rhesus macaques, evaluating for the first time the therapeutic potential of lentiviral GT in this unique LSD model. We showed favorable safety profile and consistent pattern of LV transduction and enzyme biodistribution in the two models, supporting the robustness of the proposed GT platform. We documented moderate inflammation at the injection sites, mild immune response to vector particles in few treated animals, no indication of immune response against transgenic products, and no molecular evidence of insertional genotoxicity. Efficient gene transfer in neurons, astrocytes, and oligodendrocytes close to the injection sites resulted in robust production and extensive spreading of transgenic enzymes in the whole CNS and in CSF, leading to supraphysiological ARSA activity in normal NHP and close to physiological GALC activity in the Krabbe NHP, in which biological efficacy was associated with preliminary indication of therapeutic benefit. These results support the rationale for the clinical translation of intracerebral lentiviral GT to address CNS pathology in MLD, GLD, and other neurodegenerative LSD. |
| format | Article |
| id | doaj-art-df4a76df4d1e46e5afca6e405d504c4a |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-df4a76df4d1e46e5afca6e405d504c4a2025-08-20T03:43:30ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-03-018548951010.15252/emmm.201505850Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe‐affected non‐human primates by intracerebral lentiviral gene therapyVasco Meneghini0Annalisa Lattanzi1Luigi Tiradani2Gabriele Bravo3Francesco Morena4Francesca Sanvito5Andrea Calabria6John Bringas7Jeanne M Fisher‐Perkins8Jason P Dufour9Kate C Baker10Claudio Doglioni11Eugenio Montini12Bruce A Bunnell13Krystof Bankiewicz14Sabata Martino15Luigi Naldini16Angela Gritti17San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific InstituteDepartment of Chemistry, Biology and Biotechnologies, Biochemistry and Molecular Biology Unit, University of PerugiaAnatomy and Histopathology Department, San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific InstituteUniversity of California San Francisco (UCSF)Division of Regenerative Medicine, Tulane National Primate Research CenterDivision of Regenerative Medicine, Tulane National Primate Research CenterDivision of Regenerative Medicine, Tulane National Primate Research CenterAnatomy and Histopathology Department, San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific InstituteDivision of Regenerative Medicine, Tulane National Primate Research CenterUniversity of California San Francisco (UCSF)Department of Chemistry, Biology and Biotechnologies, Biochemistry and Molecular Biology Unit, University of PerugiaSan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific InstituteAbstract Metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD or Krabbe disease) are severe neurodegenerative lysosomal storage diseases (LSD) caused by arylsulfatase A (ARSA) and galactosylceramidase (GALC) deficiency, respectively. Our previous studies established lentiviral gene therapy (GT) as a rapid and effective intervention to provide pervasive supply of therapeutic lysosomal enzymes in CNS tissues of MLD and GLD mice. Here, we investigated whether this strategy is similarly effective in juvenile non‐human primates (NHP). To provide proof of principle for tolerability and biological efficacy of the strategy, we established a comprehensive study in normal NHP delivering a clinically relevant lentiviral vector encoding for the human ARSA transgene. Then, we injected a lentiviral vector coding for the human GALC transgene in Krabbe‐affected rhesus macaques, evaluating for the first time the therapeutic potential of lentiviral GT in this unique LSD model. We showed favorable safety profile and consistent pattern of LV transduction and enzyme biodistribution in the two models, supporting the robustness of the proposed GT platform. We documented moderate inflammation at the injection sites, mild immune response to vector particles in few treated animals, no indication of immune response against transgenic products, and no molecular evidence of insertional genotoxicity. Efficient gene transfer in neurons, astrocytes, and oligodendrocytes close to the injection sites resulted in robust production and extensive spreading of transgenic enzymes in the whole CNS and in CSF, leading to supraphysiological ARSA activity in normal NHP and close to physiological GALC activity in the Krabbe NHP, in which biological efficacy was associated with preliminary indication of therapeutic benefit. These results support the rationale for the clinical translation of intracerebral lentiviral GT to address CNS pathology in MLD, GLD, and other neurodegenerative LSD.https://doi.org/10.15252/emmm.201505850braingene therapylentiviral vectorsleukodystrophynon‐human primates |
| spellingShingle | Vasco Meneghini Annalisa Lattanzi Luigi Tiradani Gabriele Bravo Francesco Morena Francesca Sanvito Andrea Calabria John Bringas Jeanne M Fisher‐Perkins Jason P Dufour Kate C Baker Claudio Doglioni Eugenio Montini Bruce A Bunnell Krystof Bankiewicz Sabata Martino Luigi Naldini Angela Gritti Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe‐affected non‐human primates by intracerebral lentiviral gene therapy EMBO Molecular Medicine brain gene therapy lentiviral vectors leukodystrophy non‐human primates |
| title | Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe‐affected non‐human primates by intracerebral lentiviral gene therapy |
| title_full | Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe‐affected non‐human primates by intracerebral lentiviral gene therapy |
| title_fullStr | Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe‐affected non‐human primates by intracerebral lentiviral gene therapy |
| title_full_unstemmed | Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe‐affected non‐human primates by intracerebral lentiviral gene therapy |
| title_short | Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe‐affected non‐human primates by intracerebral lentiviral gene therapy |
| title_sort | pervasive supply of therapeutic lysosomal enzymes in the cns of normal and krabbe affected non human primates by intracerebral lentiviral gene therapy |
| topic | brain gene therapy lentiviral vectors leukodystrophy non‐human primates |
| url | https://doi.org/10.15252/emmm.201505850 |
| work_keys_str_mv | AT vascomeneghini pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT annalisalattanzi pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT luigitiradani pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT gabrielebravo pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT francescomorena pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT francescasanvito pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT andreacalabria pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT johnbringas pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT jeannemfisherperkins pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT jasonpdufour pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT katecbaker pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT claudiodoglioni pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT eugeniomontini pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT bruceabunnell pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT krystofbankiewicz pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT sabatamartino pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT luiginaldini pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy AT angelagritti pervasivesupplyoftherapeuticlysosomalenzymesinthecnsofnormalandkrabbeaffectednonhumanprimatesbyintracerebrallentiviralgenetherapy |