Molecular Therapy: Methods & Clinical Development (Dec 2022)

A first-in-human phase I/IIa gene transfer clinical trial for Duchenne muscular dystrophy using rAAVrh74.MCK.GALGT2

  • Kevin M. Flanigan,
  • Tatyana A. Vetter,
  • Tabatha R. Simmons,
  • Megan Iammarino,
  • Emma C. Frair,
  • Federica Rinaldi,
  • Louis G. Chicoine,
  • Johan Harris,
  • John P. Cheatham,
  • Sharon L. Cheatham,
  • Brian Boe,
  • Megan A. Waldrop,
  • Deborah A. Zygmunt,
  • Davin Packer,
  • Paul T. Martin

Journal volume & issue
Vol. 27
pp. 47 – 60

Abstract

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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.

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