A first-in-human phase I/IIa gene transfer clinical trial for Duchenne muscular dystrophy using rAAVrh74.MCK.GALGT2
© 2022 The Authors..
In a phase 1/2, open-label dose escalation trial, we delivered rAAVrh74.MCK.GALGT2 (also B4GALNT2) bilaterally to the legs of two boys with Duchenne muscular dystrophy using intravascular limb infusion. Subject 1 (age 8.9 years at dosing) received 2.5 × 1013 vector genome (vg)/kg per leg (5 × 1013 vg/kg total) and subject 2 (age 6.9 years at dosing) received 5 × 1013 vg/kg per leg (1 × 1014 vg/kg total). No serious adverse events were observed. Muscle biopsy evaluated 3 or 4 months post treatment versus baseline showed evidence of GALGT2 gene expression and GALGT2-induced muscle cell glycosylation. Functionally, subject 1 showed a decline in 6-min walk test (6MWT) distance; an increase in time to run 100 m, and a decline in North Star Ambulatory Assessment (NSAA) score until ambulation was lost at 24 months. Subject 2, treated at a younger age and at a higher dose, demonstrated an improvement over 24 months in NSAA score (from 20 to 23 points), an increase in 6MWT distance (from 405 to 478 m), and only a minimal increase in 100 m time (45.6-48.4 s). These data suggest preliminary safety at a dose of 1 × 1014 vg/kg and functional stabilization in one patient.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
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| Enthalten in: |
Molecular therapy. Methods & clinical development - 27(2022) vom: 08. Dez., Seite 47-60 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Flanigan, Kevin M [VerfasserIn] |
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| Links: |
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| Themen: |
AAV |
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| Anmerkungen: |
Date Revised 03.02.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.omtm.2022.08.009 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM347024440 |
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| 100 | 1 | |a Flanigan, Kevin M |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A first-in-human phase I/IIa gene transfer clinical trial for Duchenne muscular dystrophy using rAAVrh74.MCK.GALGT2 |
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| 520 | |a © 2022 The Authors. | ||
| 520 | |a In a phase 1/2, open-label dose escalation trial, we delivered rAAVrh74.MCK.GALGT2 (also B4GALNT2) bilaterally to the legs of two boys with Duchenne muscular dystrophy using intravascular limb infusion. Subject 1 (age 8.9 years at dosing) received 2.5 × 1013 vector genome (vg)/kg per leg (5 × 1013 vg/kg total) and subject 2 (age 6.9 years at dosing) received 5 × 1013 vg/kg per leg (1 × 1014 vg/kg total). No serious adverse events were observed. Muscle biopsy evaluated 3 or 4 months post treatment versus baseline showed evidence of GALGT2 gene expression and GALGT2-induced muscle cell glycosylation. Functionally, subject 1 showed a decline in 6-min walk test (6MWT) distance; an increase in time to run 100 m, and a decline in North Star Ambulatory Assessment (NSAA) score until ambulation was lost at 24 months. Subject 2, treated at a younger age and at a higher dose, demonstrated an improvement over 24 months in NSAA score (from 20 to 23 points), an increase in 6MWT distance (from 405 to 478 m), and only a minimal increase in 100 m time (45.6-48.4 s). These data suggest preliminary safety at a dose of 1 × 1014 vg/kg and functional stabilization in one patient | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AAV | |
| 650 | 4 | |a B4GALNT | |
| 650 | 4 | |a Duchenne muscular dystrophy | |
| 650 | 4 | |a GALGT2 | |
| 650 | 4 | |a gene therapy | |
| 700 | 1 | |a Vetter, Tatyana A |e verfasserin |4 aut | |
| 700 | 1 | |a Simmons, Tabatha R |e verfasserin |4 aut | |
| 700 | 1 | |a Iammarino, Megan |e verfasserin |4 aut | |
| 700 | 1 | |a Frair, Emma C |e verfasserin |4 aut | |
| 700 | 1 | |a Rinaldi, Federica |e verfasserin |4 aut | |
| 700 | 1 | |a Chicoine, Louis G |e verfasserin |4 aut | |
| 700 | 1 | |a Harris, Johan |e verfasserin |4 aut | |
| 700 | 1 | |a Cheatham, John P |e verfasserin |4 aut | |
| 700 | 1 | |a Cheatham, Sharon L |e verfasserin |4 aut | |
| 700 | 1 | |a Boe, Brian |e verfasserin |4 aut | |
| 700 | 1 | |a Waldrop, Megan A |e verfasserin |4 aut | |
| 700 | 1 | |a Zygmunt, Deborah A |e verfasserin |4 aut | |
| 700 | 1 | |a Packer, Davin |e verfasserin |4 aut | |
| 700 | 1 | |a Martin, Paul T |e verfasserin |4 aut | |
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