Genetic modifiers in Duchenne muscular dystrophy: Testing candidates in the vamorolone trials enrolling young, steroid naïve participants


Clinical Trials

Poster Number: M189


Utkarsh Dang, PhD, Carleton University, Daniele Sabbatini, University of Padova, Luca Bello, PhD, OSPEDALE UNIVERSITARIO DI PADOVA - CLINICA NEUROLOGIA, Elena Pegoraro, PhD, University of Padova, Paula Clemens, MD, University of Pittsburgh, Michela Guglieri, Newcastle University and Newcastle Hospitals NHS Foundation Trust, VBP15-004 Investigators, CINRG, Eric Hoffman, PhD, Binghamton University, Binghamton, NY, USA

Background: Variability is seen in the onset and progression of boys living with Duchenne muscular dystrophy (DMD). Known causes of variability include corticosteroid treatment (age of initiation, dose, treatment regimen), DMD gene mutation variants, socioeconomic status, and genetic modifiers. To date, studies of genetic modifiers have been carried out in natural history studies and older participants where variability in corticosteroid treatment regimens is a confounding factor.
Objectives: To study the effects of candidate genetic modifiers on motor outcomes in a narrow age range of steroid naïve boys at baseline.
Methods: Participants (4 to <7 years) in the VBP15-002/003 trial (n=48) and VBP15-004 trial (n=121) were studied. DNA samples were genotyped using Illumina GDA-PGx platform (GlobalDiversity Array with enhanced pharmacogenomics content), with a data mask applied to analyze only previously reported candidate genetic modifier loci (LTBP4, SPP1, ACTN3, CD40, ADRB2, TNFRSF10, THBS1, DYNLT5 [TCTEX1D1]). Genotype associations were studied for motor outcomes (time to stand velocity, time to run/walk 10 meters velocity, 6-minute walk distance, time to climb 4 stairs velocity, and North Star Ambulatory Assessment), at baseline. To minimize measurement error, measurements taken in a short window of time were averaged to obtain a robust baseline measurement. Linear models were used along with multiple testing correction for each modifier across 5 outcomes. Results: Baseline clinical outcomes were distributed similarly across the two studies. LTBP4 genotype was statistically significantly associated with all five motor outcomes while DYNLT5 genotype was associated with baseline time to stand velocity and time to climb 4 stairs velocity (p<0.05). Conclusions: Genotype associations of LTBP4 and DYNLT5 loci with motor outcomes were seen in a cohort of steroid-naïve DMD boys, age 4 to <7 years. Future studies will investigate the further relevance of candidate genetic modifiers.