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Sci Rep. 2017 Dec 20;7(1):17888. doi: 10.1038/s41598-017-17982-y.

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

Author information

1
BioMarin Nederland BV, J.H. Oortweg 21, 2333 CH, Leiden, The Netherlands.
2
Department of Human Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
3
John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
4
Department of Medical Statistics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
5
Department of Neurology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
6
Department of Proteomics, School of Biotechnology, KTH-Royal Institute of Technology, Stockholm, Sweden.
7
Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Institute of Child Health, London, UK.
8
Child Neurology, University Hospitals Leuven, Leuven, Belgium.
9
Department of Pediatrics, University of Gothenburg, Queen Silvia Children's Hospital, Gothenburg, Sweden.
10
Department of Human Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. p.spitali@lumc.nl.

Abstract

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.

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