The Failed Clinical Story of Myostatin Inhibitors against Duchenne Muscular Dystrophy: Exploring the Biology behind the Battle.

Emma Rybalka,Cara A Timpani,Dean G Campelj,Ryan M Bagaric,Alan Hayes,Danielle A Debruin

doi:10.3390/cells9122657

Abstract

Myostatin inhibition therapy has held much promise for the treatment of muscle wasting disorders. This is particularly true for the fatal myopathy, Duchenne Muscular Dystrophy (DMD). Following on from promising pre-clinical data in dystrophin-deficient mice and dogs, several clinical trials were initiated in DMD patients using different modality myostatin inhibition therapies. All failed to show modification of disease course as dictated by the primary and secondary outcome measures selected: the myostatin inhibition story, thus far, is a failed clinical story. These trials have recently been extensively reviewed and reasons why pre-clinical data collected in animal models have failed to translate into clinical benefit to patients have been purported. However, the biological mechanisms underlying translational failure need to be examined to ensure future myostatin inhibitor development endeavors do not meet with the same fate. Here, we explore the biology which could explain the failed translation of myostatin inhibitors in the treatment of DMD.

Highlights

Since McPherron’s initial discovery of the mighty mouse [1] and the subsequent clinical case report of an infant with uncharacteristic muscling and superhuman strength caused by mutations in the myostatin (growth differentiation factor 8 (GDF-8)) gene (MSTN) [2], researchers and drug companies have been in a race to develop drugs targeted against myostatin protein to treat muscle wasting conditions
These were: (1) the distinct differences in native myostatin levels in mice compared to humans; (2) disparity in the proportional basal suppression of circulating myostatin between wild-type/healthy and mdx/Duchenne Muscular Dystrophy (DMD) muscles; and (3) the confounding effects of standard of care corticosteroid treatment in DMD patients which was never extensively tested in pre-clinical animal trials
The dramatic impact of loss of function myostatin mutations on muscle mass and strength accretion, which are probably most profoundly influential during embryonic development, must be balanced against the capacity of drugs to resist skeletal muscle wasting driven by a plethora of stimuli in the post-natal environment

Summary

Introduction

Since McPherron’s initial discovery of the mighty mouse [1] and the subsequent clinical case report of an infant with uncharacteristic muscling and superhuman strength caused by mutations in the myostatin (growth differentiation factor 8 (GDF-8)) gene (MSTN) [2], researchers and drug companies have been in a race to develop drugs targeted against myostatin protein to treat muscle wasting conditions. While “positive results bias”, a bias in part due to pharmaceutical company funded studies or because authors are more likely to submit—and journals more likely to accept—positive as opposed to negative research findings, might be influential in the failed translation of pharmacological myostatin inhibitors for DMD, the Wagner paper provided several key biological reasons for unsuccessful translation between pre-clinical and clinical studies [4] These were: (1) the distinct differences in native myostatin levels in mice compared to humans (by ~10 fold); (2) disparity in the proportional basal suppression of circulating myostatin between wild-type/healthy and mdx/DMD muscles (skeletal muscle myostatin is 25% of wild-type levels in mdx mice compared to 8% of healthy control levels in DMD patients); and (3) the confounding effects of standard of care corticosteroid treatment in DMD patients which was never extensively tested in pre-clinical animal trials. We discuss other potential factors which might alternatively explain the failed translation of myostatin inhibitor drugs, such as the important regulatory role myostatin plays on metabolism and the important role electrical stimulation plays in mechanotransduction signalling of muscle growth during myostatin inhibition, with important implications for future drug development programs

Myostatin Is Differentially Expressed in Mice and Humans

Myostatin Inhibition Enhances Muscle Mass but Not Function

Myostatin Inhibition Interferes with Muscle Metabolism and Endurance

Corticosteroids Interfere with Myostatin Inhibition

Findings

Conclusions