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. 2024 Sep 16;25(1):342.
doi: 10.1186/s12931-024-02966-0.

An algorithm for discontinuing mechanical ventilation in boys with x-linked myotubular myopathy after positive response to gene therapy: the ASPIRO experience

Robert J Graham  1 , Reshma Amin  2 , Nadir Demirel  3 , Lisa Edel  4 , Charlotte Lilien  5   6 , Victoria MacBean  7 , Gerrard F Rafferty  8 , Hemant Sawnani  9   10 , Carola Schön  11 , Barbara K Smith  12 , Faiza Syed  2 , Micaela Sarazen  13 , Suyash Prasad  13 , Salvador Rico  13 , Geovanny F Perez  14
Affiliations

An algorithm for discontinuing mechanical ventilation in boys with x-linked myotubular myopathy after positive response to gene therapy: the ASPIRO experience

Robert J Graham et al. Respir Res. .

Abstract

X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy. Most (80%) children with XLMTM have profound muscle weakness and hypotonia at birth resulting in severe respiratory insufficiency, the inability to sit up, stand or walk, and early mortality. At birth, 85-90% of children with XLMTM require mechanical ventilation, with more than half requiring invasive ventilator support. Historically, ventilator-dependent children with neuromuscular-derived respiratory failure of this degree and nature, static or progressive, are not expected to achieve complete independence from mechanical ventilator support. In the ASPIRO clinical trial (NCT03199469), participants receiving a single intravenous dose of an investigational gene therapy (resamirigene bilparvovec) started showing significant improvements in daily hours of ventilation support compared with controls by 24 weeks post-dosing, and 16 of 24 dosed participants achieved ventilator independence between 14 and 97 weeks after dosing. At the time, there was no precedent or published guidance for weaning chronically ventilated children with congenital neuromuscular diseases off mechanical ventilation. When the first ASPIRO participants started showing dramatically improved respiratory function, the investigators initiated efforts to safely wean them off ventilator support, in parallel with primary protocol respiratory outcome measures. A group of experts in respiratory care and physiology and management of children with XLMTM developed an algorithm to safely wean children in the ASPIRO trial off mechanical ventilation as their respiratory muscle strength increased. The algorithm developed for this trial provides recommendations for assessing weaning readiness, a stepwise approach to weaning, and monitoring of children during and after the weaning process.

Keywords: Neuromuscular disorder; Ventilator independence; Ventilator weaning; X-linked myotubular myopathy.

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Conflict of interest statement

Robert J. Graham reports consulting fees for trial design, outcomes assessments, and advisory board participation from Astellas Gene Therapies (formerly Audentes Therapeutics). Reshma Amin reports grant support from Canadian Institute of Health Research, Muscular Dystrophy Canada, Baxter Foundation, Boehringer-Ingelheim, VHS HomeHealthCare, Medigas, and Proresp; steering committee membership for Home Ventilation and Sleep Network: CHEST; and Scientific Officer for the Ontario Lung Health Foundation. Nadir Demirel reports travel reimbursement from Astellas Gene Therapies (formerly Audentes Therapeutics). Lisa Edel reports consulting fees from Roche, Biogen and Novartis; payment or honoraria from Sanofi, Roche and Neurology Academy; and travel reimbursement from Roche. Charlotte Lilien reports consulting fees, honoraria, funding for meeting-related travel, and/or advisory board participation from Astellas Gene Therapies (formerly Audentes Therapeutics), Roche, Biogen, Novartis, Sysnav, AFEHM, ATOM, Aparito and Scholar Rock. Victoria MacBean reports study funding, a research grant, and consulting fees to herself and to her institution from Astellas Gene Therapies (formerly Audentes Therapeutics). Gerrard F. Rafferty, Carola Schön and Faiza Syed report no competing interests relevant to this paper. Hemant Sawnani reports consulting fees for trial design, outcomes assessments, and advisory board participation from Astellas Gene Therapies (formerly Audentes Therapeutics). Barbara K. Smith reports prior research grant support from Astellas Gene Therapies (formerly Audentes Therapeutics). Micaela Sarazen is an employee of Astellas Gene Therapies (formerly Audentes Therapeutics). Suyash Prasad and Salvador Rico were employees and stockholders at Astellas Gene Therapies (formerly Audentes Therapeutics) at the time of this research. Geovanny F. Perez reports consulting fees and funding for meeting-related travel from Astellas Gene Therapies (formerly Audentes Therapeutics).

Figures

Fig. 1
Fig. 1
Algorithm for Weaning ASPIRO Dosed Participants Off of Invasive/Transtracheal Mechanical Ventilation
See this image and copyright information in PMC

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