Elicit: Predictive Markers for NSAA/6MWT in Dystrophinopathies (public)
Predictive Markers for NSAA/6MWT in Dystrophinopathies
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. More on methods
- Papers identified with Elicit search: n = 997
- Papers screened using: Population Type, Biomarker Measurements, Functional Outcomes, Study Duration, Study Design, Baseline Data, Research Type: n = 997
- Papers screened out: n = 957
- Papers included for extraction: n = 40
Paper search
Using your research question “Do micro-dystrophin expression and CK decline at 12 months predict NSAA/6MWT at 24–36 months?”, we searched across over 126 million academic papers from the Semantic Scholar corpus. We retrieved the 997 papers most relevant to the query.
Screening
We screened in sources based on their abstracts that met these 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)?
Data extraction
We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.
Study Design:
- Describe the type of study design used. Look in the methods section for specific details about the study’s approach. Possible designs include:
- Prospective cohort
- Retrospective chart review
- Open-label extension study
- Matched control study
Participant Characteristics:
Extract the following details about participants:
- Total number of participants
- Number of participants in each treatment/control group
- Age range or mean age
- Genetic mutation details (specifically exon 51 amenability)
- Baseline functional status (e.g., 6-minute walk test distance, North Star Ambulatory Assessment score)
Intervention Details:
Record specific details about the intervention:
- Drug/treatment name
- Dosage (mg/kg/week)
- Administration route
- Duration of treatment
- Frequency of administration
Outcome Measures:
Extract the specific outcome measures related to the research question:
- Micro-dystrophin expression (method of measurement, time points)
- Creatine kinase (CK) levels (time points of measurement)
- North Star Ambulatory Assessment (NSAA) scores
- 6-Minute Walk Test (6MWT) distances
Follow-up Duration:
Record:
- Total study duration
- Duration of active intervention
- Follow-up periods for key outcome measurements
- Specific time points for outcome assessments (e.g., 12 months, 24-36 months)
Key Findings:
Extract the primary findings related to:
- Changes in micro-dystrophin expression
- CK level changes
- Functional outcomes (NSAA and 6MWT)
- Comparisons to control or natural history groups
Results
Characteristics of Included Studies
| Study | Study Design | Patient Population | Measurement Methods | Primary Outcomes | Full text retrieved |
|---|---|---|---|---|---|
| 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 | No |
| 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 | Yes |
| Pascual-Morena et al., 2020 | Systematic review/meta-analysis | Children/adolescents with Duchenne muscular dystrophy | Pooled clinical trial data | Functional outcomes, dystrophin expression | No |
| 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 | No |
| 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 | No |
| 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 | No |
| Mendell et al., 2013 | Randomized controlled trial, open-label extension | 12 boys, 7–13 years, exon 51 amenable | 6-minute walk test | Efficacy, safety | No |
| 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 | No |
| 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 | No |
| 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 | No |
Effects
Predictive Markers at 12 Months
Micro-dystrophin Expression Patterns
| Study | Marker Type | Measurement Time | Value Range | Correlation with Outcomes |
|---|---|---|---|---|
| Mendell et al., 2021a | Micro-dystrophin | 12 weeks | Robust expression, correct localization | Associated with North Star Ambulatory Assessment improvement |
| Goemans et al., 2016 | Dystrophin | 24, 68/72 weeks | Detected in all biopsies | No direct correlation found |
| Rao et al., 2021 | Micro-dystrophin | 90 days | 5–17.5% of normal (Western blot), 10–70% fibers (immunofluorescence) | Associated with functional stabilization |
| Mendell et al., 2021b | Micro-dystrophin | 12 weeks | Primary endpoint met | Associated with North Star Ambulatory Assessment in 4–5 year subgroup |
| Mendell et al., 2023a | Micro-dystrophin | 12, 60 weeks | Achieved in all patients | Associated with North Star Ambulatory Assessment maintenance |
| Zaidman et al., 2021 | Micro-dystrophin | 12 weeks | No mention found | No mention found |
| Mendell et al., 2023b | Micro-dystrophin | 12 weeks | 23.8–39.6% of normal | Associated with North Star Ambulatory Assessment stabilization |
| Flanigan et al., 2022 | GALGT2 | 3–4 months | Evidence of expression | Subject-level improvement in 1 of 2 subjects |
| Zaidman et al., 2022 | Micro-dystrophin | 12 weeks | Demonstrated | No mention found |
| Mendell et al., 2024 | Micro-dystrophin | 12 weeks | 34.3% in treated, 0% in placebo | Associated with creatine kinase decline, North Star Ambulatory Assessment trend |
Creatine Kinase Level Trends
| Study | Marker Type | Measurement Time | Value Range | Correlation with Outcomes |
|---|---|---|---|---|
| Mendell et al., 2021a | Creatine kinase | No mention found | Reduction associated with vector | Associated with North Star Ambulatory Assessment improvement |
| Mendell et al., 2024 | Creatine kinase | Baseline, 52 weeks | -4,344 units/Liter vs. placebo | Associated with micro-dystrophin, North Star Ambulatory Assessment trend |
| Finkel et al., 2018 | Muscle enzymes | ≥12 weeks | Decreased | Associated with North Star Ambulatory Assessment improvement |
| Finkel et al., 2019 | Muscle enzymes | ≥12 weeks | Decreased | Associated with functional stabilization |
| Pascual-Morena et al., 2020 | Creatine kinase | No mention found | No mention found | No mention found |
Functional Outcomes at 24–36 Months
North Star Ambulatory Assessment Progression
| Study | Outcome Measure | Time Point | Result Range | Predictive Association |
|---|---|---|---|---|
| Mendell et al., 2021a | North Star Ambulatory Assessment | Year 2 | +7.0 points | Associated with micro-dystrophin |
| Mendell et al., 2021b | North Star Ambulatory Assessment | 48 weeks | +2.5 (4–5 years, p=0.0172) | Associated with micro-dystrophin |
| Mendell et al., 2023a | North Star Ambulatory Assessment | 48, 96 weeks | +1.3 points at 48 weeks | Maintained vs. expected decline |
| Mendell et al., 2023b | North Star Ambulatory Assessment | 48, 96 weeks | +1.7 (Part 1), +1.3 (Part 2) | Associated with micro-dystrophin |
| Mendell et al., 2024 | North Star Ambulatory Assessment | 52 weeks | +2.57 (treated), +1.92 (placebo) | Non-significant group difference |
| Finkel et al., 2018 | North Star Ambulatory Assessment | 24–36 weeks | Clinically meaningful improvement | Associated with creatine kinase decline |
| Finkel et al., 2019 | North Star Ambulatory Assessment | Up to 72 weeks | Slowing of progression | Associated with muscle enzyme decline |
| Li et al., 2023 | North Star Ambulatory Assessment | 12 months | Decline from age 6 years | Natural history reference |
6-Minute Walk Test Performance
| Study | Outcome Measure | Time Point | Result Range | Predictive Association |
|---|---|---|---|---|
| Goemans et al., 2016 | 6-minute walk test | 177 weeks | +8 meters (all), +64 meters (ambulant) | Dystrophin detected |
| Pascual-Morena et al., 2020 | 6-minute walk test | 48 weeks, 3 years | +67.3 meters (48 weeks), +151 meters (3 years) | Eteplirsen, Drisapersen, Ataluren |
| Mendell et al., 2017 | 6-minute walk test | 4 years | +162 meters (p=0.0005) | Eteplirsen vs. controls |
| Mendell et al., 2016a | 6-minute walk test | 3 years | +151 meters (p<0.01) | Eteplirsen vs. controls |
| Hurley, 2016 | 6-minute walk test | 36 months | +151 meters (p<0.01) | Eteplirsen vs. controls |
| Kaye et al., 2014 | 6-minute walk test | 96 weeks | +71 meters (p≤0.001) | Eteplirsen vs. controls |
| Goemans et al., 2014 | 6-minute walk test | 96 weeks | +46 meters (open-label extension) | Drisapersen vs. placebo |
| Goemans et al., 2015c | 6-minute walk test | 96 weeks | +46 meters (drisapersen), +31 meters at 24 weeks (p=0.003) | Drisapersen vs. placebo |
| Flanigan et al., 2022 | 6-minute walk test | 24 months | +73 meters (subject 2) | GALGT2 expression |
Predictive Relationships
- Micro-dystrophin expression and CK declines are temporarily associated with improvements in NSAA and 6MWT, but no direct predictive modeling exists.
Synthesis and Limitations
- Evidence indicates temporal associations but lacks strength due to individual-level predictive modeling absence and inconsistent reporting across studies.