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.

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:
- Open-label study
- Open-label extension
- Systematic review/meta-analysis
- Prospective cohort
- Randomized controlled trial
Participant Characteristics:
- 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:
- Drug/treatment name
- Dosage (mg/kg/week)
- Administration route
- Duration of treatment
- Frequency of administration
Outcome Measures:
- 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:
- Total study duration
- Duration of active intervention
- Follow-up periods for key outcome measurements
Key Findings:
- Changes in micro-dystrophin expression
- CK level changes
- Functional outcomes (NSAA and 6MWT)

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

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
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

Micro-dystrophin was the most commonly studied marker.
In 7 of 10 studies, we found mention of an association between marker expression and functional or clinical improvement.

Creatine Kinase Level Trends

Study	Marker Type	Measurement Time	Value Range	Correlation with Outcomes
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

Creatine kinase was assessed in 3 studies, and muscle enzymes in 2 studies.

Functional Outcomes at 24–36 Months

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
Finkel et al., 2019	North Star Ambulatory Assessment	Up to 72 weeks	Slowing of progression	Associated with muscle enzyme decline

5 studies reported improvement in North Star Ambulatory Assessment scores.

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
Mendell et al., 2016a	6-minute walk test	3 years	+151 meters (p<0.01)	Eteplirsen vs. controls

All studies reported a positive result with increases in 6-minute walk test distance ranging from +8 meters to +162 meters.

Predictive Relationships

Micro-dystrophin Expression as Predictor

No study directly models micro-dystrophin expression at 12 months as a predictor of NSAA or 6-minute walk test at 24–36 months.

Creatine Kinase Decline as Predictor

No study provides direct predictive modeling.

Combined Predictive Value

No study combines micro-dystrophin expression and creatine kinase decline at 12 months in a predictive model.

Synthesis and Limitations

The findings indicate that micro-dystrophin expression and creatine kinase decline at 12 months are temporally associated with stabilization or improvement in functional outcomes in treated Duchenne muscular dystrophy populations. However, limitations include lack of individual-level predictive modeling and heterogeneity in study design.

References

Mendell, J. et al. (2023). Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy. Frontiers in Cell and Developmental Biology
Goemans, N. et al. (2016). Long-Term Efficacy, Safety, and Pharmacokinetics of Drisapersen in Duchenne Muscular Dystrophy: Results from an Open-Label Extension Study. PLoS ONE
Pascual-Morena, C. et al. (2020). Restorative treatments of dystrophin expression in Duchenne muscular dystrophy: A systematic review. Annals of Clinical and Translational Neurology.