Clinical trial NCT06337669: Characterization of DupEx2 Duchenne Muscular Dystrophy
Official title: Characterization of the Phenotypic Diversity in DupEx2 Duchenne Muscular Dystrophy and Identification of Predictive/Prognostic Markers
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Muscular Dystrophy, Duchenne
Lead sponsor: IRCCS San Raffaele
Sponsor class: OTHER
First posted: 2024-03-29
Enrollment: 26
Sex: MALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Italian DMD patients with Dup2 mutation

Brief summary: To characterize the clinical phenotype and possible predictive/prognostic factors of patients with Duchenne muscular dystrophy (DMD) due to duplication of exon 2 (Dup2). Specifically, we aim 1) to describe the progression of motor, respiratory and cardiac function; 2) to enquire if the phenotypic spectrum of Dup2 is milder than classic DMD, 3) to perform whole genome sequencing (WGS) to characterize DNA breakpoints to correlate with the phenotype; 4) to collect material for future proteomic/transcriptomic studies.

Background/Rationale DMD is caused by mutations in the DMD gene and in 11% of cases is due to duplications. The most promising therapeutic approaches include mutation-specific therapies. Notably, there is increasing evidence that specific groups of mutations may underlie different disease trajectories compared to the "average" DMD population. It is thus mandatory to have more information on genotype-phenotype correlations and patterns of progression related to different genotypes.

Dup2 is the most common DMD duplication and the only one for which a AAV-mediated exon skipping study is ongoing. Despite most case series and databases ascribe Dup2 to severe phenotype, our preliminary findings sustain that these patients have collectively a milder progression of the disease and in 1/3 of cases a significantly milder phenotype. Moreover, our attempts to reveal mechanism involved in attenuating the phenotype would confute the hypothesis of alternative spicing transcripts as previously described for DMD with deletion of exon 2.

Research design and methods Clinical information regarding a cohort of 26 Italian Dup2 patients will be collected. Differences in time to loss of ambulation compared to a DMD control group will be achieved. Finally, we will retrieve DNA for correlative WGS studies.

Anticipated output We expect that Dup2 patients present a milder DMD phenotype , which might be predicted by genomic studies.

Detailed description: The primary clinical endpoint is time to loss of ambulation (LOA).

Secondary endpoints include:

1. The change over time of the following functional measurements:

   1.1 Motor function: The 6 Minute Walk test (6MWT) and North Star Ambulatory Assessment (NSAA) including sub-items such as Time to Rise from the floor.

   1.2 Respiratory function: Forced Vital Capacity (FVC) Liters (L) and % of predicted; time to FVC% \< 50%. Time to Nocturnal Ventilation initiation.

   1,3 Cardiac function: Left ventricular ejection fraction (EF) as measured by echocardiogram.
2. To characterize DNA breakpoints in mild vs severe phenotypes

Eligibility criteria: Inclusion Criteria:

* pediatric and adult DMD patients harboring a genetically confirmed duplication of the exon 2 in the dystrophin gene

Exclusion Criteria:

* patients lacking genetic confirmation of Dup2 mutation

Primary outcomes:
measure: Age at loss of ambulation
timeFrame: 12 months
Secondary outcomes:
measure: Time test for motor function
timeFrame: 12 months
measure: Respiratory function
timeFrame: 12 months
Other outcomes:
Locations:
city: Milano
country: Italy
facility: Dept. of Neurology, IRCCS Ospedale San Raffaele
Study officials:
affiliation: IRCCS Ospedale San Raffaele
name: Stefano C Previtali, MD
role: PRINCIPAL_INVESTIGATOR
References: