AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency
N-glycanase 1 (NGLY1) Deficiency is a progressive, ultra-rare, autosomal recessive disorder with no approved therapy and five core clinical features: severe global developmental delay, hyperkinetic movement disorder, elevated liver transaminases, alacrima, and peripheral neuropathy. Here, we confirm...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050122001401 |
| _version_ | 1797990896516464640 |
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| author | Lei Zhu Brandon Tan Selina S. Dwight Brendan Beahm Matt Wilsey Brett E. Crawford Becky Schweighardt Jennifer W. Cook Thomas Wechsler William F. Mueller |
| author_facet | Lei Zhu Brandon Tan Selina S. Dwight Brendan Beahm Matt Wilsey Brett E. Crawford Becky Schweighardt Jennifer W. Cook Thomas Wechsler William F. Mueller |
| author_sort | Lei Zhu |
| collection | DOAJ |
| description | N-glycanase 1 (NGLY1) Deficiency is a progressive, ultra-rare, autosomal recessive disorder with no approved therapy and five core clinical features: severe global developmental delay, hyperkinetic movement disorder, elevated liver transaminases, alacrima, and peripheral neuropathy. Here, we confirmed and characterized the Ngly1-/-/ rat as a relevant disease model. GS-100, a gene therapy candidate, is a recombinant, single-stranded adeno-associated virus (AAV) 9 vector designed to deliver a functional copy of the human NGLY1 gene. Using the Ngly1-/- rat, we tested different administration routes for GS-100: intracerebroventricular (ICV), intravenous (IV), or the dual route (IV + ICV). ICV and IV + ICV administration resulted in widespread biodistribution of human NGLY1 DNA and corresponding mRNA and protein expression in CNS tissues. GS-100 delivered by ICV or IV + ICV significantly reduced levels of the substrate biomarker N-acetylglucosamine-asparagine (GlcNAc-Asn or GNA) in CSF and brain tissue compared with untreated Ngly1-/- rats. ICV and IV + ICV administration of GS-100 resulted in behavioral improvements in rotarod and rearing tests, whereas IV-only administration did not. IV + ICV did not provide additional benefit compared with ICV administration alone. These data provide evidence that GS-100 could be an effective therapy for NGLY1 Deficiency using the ICV route of administration. |
| first_indexed | 2024-04-11T08:43:47Z |
| format | Article |
| id | doaj.art-fc8806dc850d435e8186ae57cbee6eca |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-11T08:43:47Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-fc8806dc850d435e8186ae57cbee6eca2022-12-22T04:34:02ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012022-12-0127259271AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 DeficiencyLei Zhu0Brandon Tan1Selina S. Dwight2Brendan Beahm3Matt Wilsey4Brett E. Crawford5Becky Schweighardt6Jennifer W. Cook7Thomas Wechsler8William F. Mueller9Grace Science, LLC, Menlo Park, CA 94025, USAGrace Science, LLC, Menlo Park, CA 94025, USAGrace Science, LLC, Menlo Park, CA 94025, USAGrace Science, LLC, Menlo Park, CA 94025, USAGrace Science, LLC, Menlo Park, CA 94025, USAGrace Science, LLC, Menlo Park, CA 94025, USAGrace Science, LLC, Menlo Park, CA 94025, USAGrace Science, LLC, Menlo Park, CA 94025, USAGrace Science, LLC, Menlo Park, CA 94025, USAGrace Science, LLC, Menlo Park, CA 94025, USA; Corresponding author William F. Mueller, Grace Science, LLC, 1142 Crane Street, Ste 4, Menlo Park, CA 94025, USA.N-glycanase 1 (NGLY1) Deficiency is a progressive, ultra-rare, autosomal recessive disorder with no approved therapy and five core clinical features: severe global developmental delay, hyperkinetic movement disorder, elevated liver transaminases, alacrima, and peripheral neuropathy. Here, we confirmed and characterized the Ngly1-/-/ rat as a relevant disease model. GS-100, a gene therapy candidate, is a recombinant, single-stranded adeno-associated virus (AAV) 9 vector designed to deliver a functional copy of the human NGLY1 gene. Using the Ngly1-/- rat, we tested different administration routes for GS-100: intracerebroventricular (ICV), intravenous (IV), or the dual route (IV + ICV). ICV and IV + ICV administration resulted in widespread biodistribution of human NGLY1 DNA and corresponding mRNA and protein expression in CNS tissues. GS-100 delivered by ICV or IV + ICV significantly reduced levels of the substrate biomarker N-acetylglucosamine-asparagine (GlcNAc-Asn or GNA) in CSF and brain tissue compared with untreated Ngly1-/- rats. ICV and IV + ICV administration of GS-100 resulted in behavioral improvements in rotarod and rearing tests, whereas IV-only administration did not. IV + ICV did not provide additional benefit compared with ICV administration alone. These data provide evidence that GS-100 could be an effective therapy for NGLY1 Deficiency using the ICV route of administration.http://www.sciencedirect.com/science/article/pii/S2329050122001401MT: NGLY1NGLY1 Deficiencygene therapyCNSGNAintracerebroventricular |
| spellingShingle | Lei Zhu Brandon Tan Selina S. Dwight Brendan Beahm Matt Wilsey Brett E. Crawford Becky Schweighardt Jennifer W. Cook Thomas Wechsler William F. Mueller AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency Molecular Therapy: Methods & Clinical Development MT: NGLY1 NGLY1 Deficiency gene therapy CNS GNA intracerebroventricular |
| title | AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency |
| title_full | AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency |
| title_fullStr | AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency |
| title_full_unstemmed | AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency |
| title_short | AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency |
| title_sort | aav9 ngly1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of ngly1 deficiency |
| topic | MT: NGLY1 NGLY1 Deficiency gene therapy CNS GNA intracerebroventricular |
| url | http://www.sciencedirect.com/science/article/pii/S2329050122001401 |
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