Elicit: Predictive Markers for NSAA/6MWT in Dystrophinopathies (public)
Do micro-dystrophin expression and CK decline at 12 months predict NSAA/6MWT at 24–36 months?
Abstract
Micro‐dystrophin expression measured within the first 12 months is reported to parallel later ambulatory function in Duchenne muscular dystrophy. Studies document that robust micro‐dystrophin induction—ranging from approximately 24% to nearly 40% of normal levels measured at 12 weeks to 12 months—is accompanied by North Star Ambulatory Assessment (NSAA) improvements of +1.3 to +7.0 points at 48 weeks to 2 years. In several trials, declines in creatine kinase (e.g., a reduction of about 4,344 units/L) track with such functional gains, and interventions have produced 6‐minute walk test improvements of up to +162 meters.
No study directly models micro‐dystrophin expression or creatine kinase decline as individual predictors of later NSAA or 6‐minute walk test performance, nor do any combine these markers in a single analysis. Instead, group‐level associations and temporal trends consistently link early biomarker shifts with later stabilization or improvement in ambulation outcomes.
Methods
We analyzed 40 sources from an initial pool of 997, using 7 screening criteria. Each paper was reviewed for 6 key aspects that mattered most to the research question.
Screening Criteria
- Population Type: Does the study include human patients diagnosed with Duchenne muscular dystrophy (DMD) aged 4-18 years?
- Biomarker Measurements: Does the study measure both micro-dystrophin expression levels AND creatine kinase (CK) levels at 12 months?
- Functional Outcomes: Does the study report either NSAA or 6MWT measurements (or both) at 24-36 months using standardized protocols?
- Study Duration: Does the study have a follow-up period of at least 24 months?
- Study Design: Is the study either a clinical trial, cohort study, or systematic review with 10 or more patients?
- Baseline Data: Does the study include baseline measurements of both micro-dystrophin and CK levels?
- Research Type: Is the study conducted on human subjects (not animal or in vitro research)?
Results
Characteristics of Included Studies
| Study | Study Design | Patient Population | Measurement Methods | Primary Outcomes |
|---|---|---|---|---|
| Mendell et al., 2021a | Open-label study | 4 ambulatory boys, 4–7 years, Duchenne muscular dystrophy | Immunofluorescence, Western blot (micro-dystrophin), North Star Ambulatory Assessment | Safety, micro-dystrophin expression, North Star Ambulatory Assessment |
| Goemans et al., 2016 | Open-label extension | 12 boys, mean 9.5 years, Duchenne muscular dystrophy, exon 51 amenable | Muscle biopsy (dystrophin), 6-minute walk test | Long-term efficacy, safety, pharmacokinetics |
| Pascual-Morena et al., 2020 | Systematic review/meta-analysis | Children/adolescents with Duchenne muscular dystrophy | Pooled clinical trial data | Functional outcomes, dystrophin expression |
| Rao et al., 2021 | Prospective cohort, open-label | Duchenne muscular dystrophy patients, age not reported | Western blot (micro-dystrophin), functional tests | Safety, micro-dystrophin, function |
| Goemans et al., 2015a | Prospective cohort | 269 boys, 3–18 years, Duchenne muscular dystrophy | 6-minute walk test, North Star Ambulatory Assessment, timed function tests | Natural history, biomarkers |
| Mendell et al., 2021b | Randomized controlled trial, crossover, open-label extension | 41 boys, 4–7 years, Duchenne muscular dystrophy | Western blot (micro-dystrophin), North Star Ambulatory Assessment | Safety, efficacy |
| Mendell et al., 2013 | Randomized controlled trial, open-label extension | 12 boys, 7–13 years, exon 51 amenable | 6-minute walk test | Efficacy, safety |
| Mendell et al., 2014 | Prospective cohort, randomized controlled trial elements | 12 boys, 7–13 years, exon 51 amenable | 6-minute walk test, pulmonary function test | Efficacy, safety |
| Mendell et al., 2023a | Randomized controlled trial, crossover, open-label extension | 41 boys, ≥4–<8 years, Duchenne muscular dystrophy | Western blot (micro-dystrophin), North Star Ambulatory Assessment | Safety, efficacy |
| Zaidman et al., 2021 | Open-label, Phase 1b | 20 boys, 4–7 years, Duchenne muscular dystrophy | Western blot, immunofluorescence (micro-dystrophin), North Star Ambulatory Assessment | Expression, safety |
Predictive Markers at 12 Months
- Micro-dystrophin expression tends to correlate with functional outcomes.
- Creatine kinase reduction is associated with North Star Ambulatory Assessment improvement.
Functional Outcomes at 24–36 Months
- Improvements in NSAA have been documented, showing associations with both micro-dystrophin expression and creatine kinase levels.
Key Findings
- Micro-dystrophin Expression: Higher levels generally associate with better functional outcomes.
- Creatine Kinase Trends: Declines correlate with improvements in both NSAA and 6MWT.
Synthesis and Limitations
The available evidence indicates that micro-dystrophin expression and creatine kinase decline at 12 months are associated with stabilization or improvement in North Star Ambulatory Assessment and 6-minute walk test at 24–36 months in treated Duchenne muscular dystrophy populations. However, the absence of individual-level predictive modeling limits the conclusions.