Journal Article

Evaluation of serum MMP-9 as predictive biomarker for antisense therapy in Duchenne

Aartsma-Rus, A., Lochmüller, H., Kozaczynska, K., de Bruijn, P., Al-Khalili Szigyarto, C., Lourbakos, A., Ayoglu, B., Verschuuren, J. J., Goemans, N., de Kimpe, S., Spitali, P., Hiller, M., Nilsson, P., Koeks, Z., de Klerk, D., Campion, G., Muntoni, F., Niks, E. H., Jean-Baptiste, R., Wolterbeek, R., Tulinius, M., Yau, N., t Hoen, Peter A. C., Nadarajah, V. D., Reza, M., Zaharieva, I.

2017

Overview

Duchenne Muscular Dystrophy (DMD) is a severe muscle disorder caused by lack of dystrophin. Predictive biomarkers able to anticipate response to the therapeutic treatments aiming at dystrophin re-expression are lacking. The objective of this study is to investigate Matrix Metalloproteinase-9 (MMP-9) as predictive biomarker for Duchenne. Two natural history cohorts were studied including 168 longitudinal samples belonging to 66 patients. We further studied 1536 samples obtained from 3 independent clinical trials with drisapersen, an antisense oligonucleotide targeting exon 51: an open label study including 12 patients; a phase 3 randomized, double blind, placebo controlled study involving 186 patients; an open label extension study performed after the phase 3. Analysis of natural history cohorts showed elevated MMP-9 levels in patients and a significant increase over time in longitudinal samples. MMP-9 decreased in parallel to clinical stabilization in the 12 patients involved in the open label study. The phase 3 study and subsequent extension study clarified that the decrease in MMP-9 levels was not predictive of treatment response. These data do not support the inclusion of serum MMP-9 as predictive biomarker for DMD patients.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/109/1942 / 631/154/53/2423 / 692/53/2423 / 692/617/375/374 / 82/80 / Adolescent / Adult / Antisense oligonucleotides / Biomarkers / Biomarkers - blood / Child / Child, Preschool / Clinical trials / Clinical Trials, Phase III as Topic / Double-Blind Method / Duchenne's muscular dystrophy / Dystrophin / Dystrophin - genetics / Dystrophy / Exons - genetics / Female / Gelatinase B / Humanities and Social Sciences / Humans / Longitudinal Studies / Male / Matrix metalloproteinase / Matrix Metalloproteinase 9 - blood / Metalloproteinase / multidisciplinary / Muscular Dystrophy, Duchenne - blood / Muscular Dystrophy, Duchenne - genetics / Oligonucleotides, Antisense - genetics / Pediatrics / Pediatrik / Randomized Controlled Trials as Topic / Science / Science (multidisciplinary) / Young Adult