BACKGROUND: XLMTM, caused by mutations in the MTM1 gene, is characterized by profound muscle weakness, respiratory failure, and early death. OBJECTIVES: ASPIRO is an ongoing, open-label, randomized study (NCT03199469) evaluating safety/efficacy of AT132, an investigational gene therapy for delivery of functional MTM1 gene copies. RESULTS: XLMTM patients (pts), BACKGROUND: XLMTM, caused by mutations in the MTM1 gene, is characterized by profound muscle weakness, respiratory failure, and early death. OBJECTIVES: ASPIRO is an ongoing, open-label, randomized study (NCT03199469) evaluating safety/efficacy of AT132, an investigational gene therapy for delivery of functional MTM1 gene copies. RESULTS: XLMTM patients (pts), BACKGROUND: XLMTM, caused by mutations in the MTM1 gene, is characterized by profound muscle weakness, respiratory failure, and early death. OBJECTIVES: ASPIRO is an ongoing, open-label, randomized study (NCT03199469) evaluating safety/efficacy of AT132, an investigational gene therapy for delivery of functional MTM1 gene copies. RESULTS: XLMTM patients (pts), £ 7 years old, were randomized to treatment or delayed-treatment control (ctrl) and enrolled into ascending dose cohorts to receive a single AT132 infusion. Data are available for 12 pts (4–72 weeks’ follow-up): 6, Cohort 1 (1x1014vg/kg); 4, Cohort 2 (3x1014vg/kg); 2, untreated ctrls. Muscle biopsy data are available for 9 treated pts: 6, Cohort 1; 3, Cohort 2. Since study initiation (Sep17) there were 82 AEs considered related/possibly related (14 serious AEs; 68 non-serious) as of 7Aug19. At baseline, all pts required 12–24 hrs/day ventilatory (vent) support, and missed critical motor milestones. Clinically meaningful changes from baseline in CHOP-INTEND and MIP scores were observed in all but one treated pt. Treated pts also achieved important motor milestones: ability to sit unassisted, raise self to stand, and walk supported or independently. There was significant and rapid reduction in vent use in all but one treated pt, with 7 treated pts reaching vent independence. These improvements contrast with the 2 untreated ASPIRO ctrls and the INCEPTUS contemporaneous external ctrl subjects (NCT02704273) in whom gains of motor skills and achievement of ventilator independence were not observed. Muscle biopsies demonstrated robust dose-dependent tissue transduction and myotubularin expression with considerable improvement in histopathology. CONCLUSIONS: AT132 has shown manageable safety profile across dose cohorts. Clinically meaningful improvements in neuromuscular and respiratory function continue through 72 weeks post-dose. An optimal dose (3×1014 vg/kg) has been selected for the study’s confirmatory phase. £ 7 years old, were randomized to treatment or delayed-treatment control (ctrl) and enrolled into ascending dose cohorts to receive a single AT132 infusion. Data are available for 12 pts (4–72 weeks’ follow-up): 6, Cohort 1 (1×1014 vg/kg); 4, Cohort 2 (3×1014 vg/kg); 2, untreated ctrls. Muscle biopsy data are available for 9 treated pts: 6, Cohort 1; 3, Cohort 2. Since study initiation (Sep17) there were 82 AEs considered related/possibly related (14 serious AEs; 68 non-serious) as of 7Aug19. At baseline, all pts required 12–24 hrs/day ventilatory (vent) support, and missed critical motor milestones. Clinically meaningful changes from baseline in CHOP-INTEND and MIP scores were observed in all but one treated pt. Treated pts also achieved important motor milestones: ability to sit unassisted, raise self to stand, and walk supported or independently. There was significant and rapid reduction in vent use in all but one treated pt, with 7 treated pts reaching vent independence. These improvements contrast with the 2 untreated ASPIRO ctrls and the INCEPTUS contemporaneous external ctrl subjects (NCT02704273) in whom gains of motor skills and achievement of ventilator independence were not observed. Muscle biopsies demonstrated robust dose-dependent tissue transduction and myotubularin expression with considerable improvement in histopathology. CONCLUSIONS: AT132 has shown manageable safety profile across dose cohorts. Clinically meaningful improvements in neuromuscular and respiratory function continue through 72 weeks post-dose. An optimal dose (3x1014vg/kg) has been selected for the study’s confirmatory phase. £ 7 years old, were randomized to treatment or delayed-treatment control (ctrl) and enrolled into ascending dose cohorts to receive a single AT132 infusion. Data are available for 12 pts (4–72 weeks’ follow-up): 6, Cohort 1 (1×1014 vg/kg); 4, Cohort 2 (3×1014 vg/kg); 2, untreated ctrls. Muscle biopsy data are available for 9 treated pts: 6, Cohort 1; 3, Cohort 2. Since study initiation (Sep17) there were 82 AEs considered related/possibly related (14 serious AEs; 68 non-serious) as of 7Aug19. At baseline, all pts required 12–24 hrs/day ventilatory (vent) support, and missed critical motor milestones. Clinically meaningful changes from baseline in CHOP-INTEND and MIP scores were observed in all but one treated pt. Treated pts also achieved important motor milestones: ability to sit unassisted, raise self to stand, and walk supported or independently. There was significant and rapid reduction in vent use in all but one treated pt, with 7 treated pts reaching vent independence. These improvements contrast with the 2 untreated ASPIRO ctrls and the INCEPTUS contemporaneous external ctrl subjects (NCT02704273) in whom gains of motor skills and achievement of ventilator independence were not observed. Muscle biopsies demonstrated robust dose-dependent tissue transduction and myotubularin expression with considerable improvement in histopathology. CONCLUSIONS: AT132 has shown manageable safety profile across dose cohorts. Clinically meaningful improvements in neuromuscular and respiratory function continue through 72 weeks post-dose. An optimal dose (3x1014vg/kg) has been selected for the study’s confirmatory phase.