ASPIRO Gene Therapy Trial in X-Linked Myotubular Myopathy (XLMTM): Update on Preliminary Efficacy and Safety Findings
Bibliographic record
Abstract
Background/Purpose: XLMTM, an ultra-rare, life-threatening myopathy is caused by mutations in MTM1 gene, leading to absent or dysfunctional myotubularin. We present updated results from ASPIRO (NCT03199469), investigating gene replacement therapy, AT132 for XLMTM. Methods: Participants were genetically confirmed XLMTM patients, required ventilator support and had no clinically significant underlying liver disease (>5× ULN ALT or AST, or hepatic peliosis by imaging). As of July 2020, efficacy data were analyzed for 16 participants ( n = 6, 1 × 10 14 vg/kg (age 0.8–4.1 years at dosing); n = 10, 3 × 10 14 vg/kg (age: 1.3–6.8 years at dosing) versus control ( n = 7). Results: At baseline, all participants required ventilator support (mean [SD] 22.4 [3.34] hours/day), and missed critical motor milestones. Treated participants had significant reductions in daily hours of ventilator dependence vs control ( p < 0.0001 for both doses); 5/6 participants at 1 × 10 14 vg/kg achieved ventilator independence. Treated participants showed significant improvements in motor function vs control; acquired and maintained several major motor milestones. Muscle biopsies demonstrated durable myotubularin expression with improved pathology scores at 48 weeks. Three participants at 3 × 10 14 vg/kg, who were relatively older and heavier vs others, experienced fatal sepsis or gastrointestinal bleeding with ongoing severe cholestatic liver dysfunction. Present understanding is that these events are related to a combination of underlying XLMTM process and gene replacement therapy. Three patient deaths are currently investigated to ensure appropriate safety monitoring of AT132. Conclusion: XLMTM patients treated with AT132 demonstrated significant improvements vs control in neuromuscular and respiratory function. Assessment of safety and efficacy is ongoing. This abstract has been submitted at the World Muscle Society Congress 2021. Publication History Publication Date: 28 October 2021 (online) © 2021. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".