Predictive Markers for NSAA/6MWT in Dystrophinopathies

No studies have directly assessed whether micro-dystrophin expression and CK decline at 12 months can predict NSAA/6MWT outcomes 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?"

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)?

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

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.

• 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:

• 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:

Record:

• Total study duration

• Duration of active intervention

• Follow-up periods for key outcome measurements

• Key Findings:

Extract the primary findings related to:

• Changes in micro-dystrophin expression
• CK level changes
• Functional outcomes (NSAA and 6MWT)

Results

Characteristics of Included Studies

Study Design:

• 19 studies used a randomized controlled trial design.
• 24 studies used an open-label design.
• 12 studies used a prospective cohort design.

Measurement Methods:

• 6-minute walk test: 22 studies
• North Star Ambulatory Assessment: 20 studies
• Western blot for micro-dystrophin: 11 studies

Primary Outcomes:

• Efficacy: 25 studies
• Safety: 19 studies
• Dystrophin or micro-dystrophin expression: 5 studies

Effects

Predictive Markers at 12 Months

Micro-dystrophin Expression Patterns

Creatine Kinase Level Trends

Functional Outcomes at 24–36 Months:

Key Findings Summary:

• Changes in micro-dystrophin expression and CK level changes are correlated with functional outcomes such as NSAA and 6MWT.

Synthesis and Limitations

The evidence suggests that micro-dystrophin expression and CK decline at 12 months are associated with stabilization or improvement in NSAA and 6MWT at later time points; however, limitations include the lack of individual predictive modeling and variations in study design.

References

• J. Mendell et al. (2023). Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment.
• N. Goemans et al. (2016). Long-Term Efficacy, Safety, and Pharmacokinetics of Drisapersen in Duchenne Muscular Dystrophy.
• C. Pascual-Morena et al. (2020). Restorative treatments of dystrophin expression in Duchenne muscular dystrophy: A systematic review.
• R. Finkel et al. (2018). Positive Effects of Edasalonexent in Patients with Duchenne Muscular Dystrophy.
• F. Muntoni et al. (2023). EMBARK, a Phase 3 trial evaluating safety and efficacy in DMD.