MICA: The role of MMP inhibitors in ameliorating muscular dystrophy

Muscular dystrophies are a set of inherited conditions that show progressive muscle wasting and loss of function such that affected individuals become wheelchair bound and suffer premature death. While medical treatment to aid the respiratory muscles and the heart both prolongs lifespan and improves quality of life, there are no treatments that prevent the inevitable progressive loss of muscle and the consequent loss of independence.

The repeated cycles of muscle damage cause inflammation and scar tissue formation and this very likely inhibits effective muscle repair. This project will test the ability of a specific inhibitor of one of the enzymes associated with this scarring process to alter the disease progression in two mouse models of muscular dystrophy.

The enzyme inhibitor was developed and tested in clinical trial for a different disease by AstraZeneca and so a lot is known about the safety of this drug. Therefore if it is effective in improving muscle function in the mice, it could be rapidly taken into clinical trial for muscular dystrophy avoiding the delays normally associated with the drug development process.

Muscular dystrophies are characterised by progressive muscle wasting and fibre loss. This is associated with changes in the composition/organisation of the extracellular matrix which itself helps to precipitate the inefficient regeneration and muscle fibre loss that characterises the later stages. There are no current treatments that prevent muscle fibre loss. We hypothesise that if matrix remodelling can be prevented by MMP inhibition during the early stages of muscular dystrophy, fibre loss will be reduced and regeneration made more efficient. This hypothesis is based upon two main findings, firstly matrix metalloproteinases (MMPs), specifically MMP9, are up-regulated in the muscle of mdx mice where they localise to areas of inflammatory infiltrate and muscle fibre degeneration and secondly that MMP inhibition has been previously shown to ameliorate muscular dystrophy in the mdx. To test this hypothesis we will use two animal models both of which are associated with progressive forms of muscular dystrophy namely; the dystrophin deficient mdx, which is a model for Duchenne Muscular Dystrophy and the FKRPMD mouse which is a model for LGMD2I. Both have disruption of the linkage between the muscle fibre and the basement membrane, the mdx does this via an alteration in a cytoskeletal protein (dystrophin) and the FKRPMD via a disruption in the binding between alpha-dystroglycan and LG domain containing proteins laminin and perlecan in the extracellular matrix. We will initially treat mice of two different stages of the disease for 3 months at three dose rates by oral gavage of AZD1236, a potent, selective, orally bio-available, MMP9/12 inhibitor that has been studied in Phase 2a clinical trials in COPD patients via oral administration. We will then select the best age and dose rate for an extended 6 month study involving exercise induced exacerbation of the pathology. The aim is to determine if AZD1236 is sufficiently effective to warrant a clinical trial.

If the project shows reduced pathology and improved function in the chosen mouse models, the ultimate beneficiaries will be the patients with muscular dystrophy and their families. The results of the studies will more immediately be of interest to clinicians who deal with muscular dystrophy patients as they will be able to evaluate the potential of the inhibition of MMP9/12 in muscular dystrophy and thus enthusiasm for involvement in clinical trials. The information will also play an important role for drug companies such as AstraZeneca in making decisions whether to proceed to clinical trial.

As the compound under investigation has already been taken to Phase 2 clinical trial in another indication, the regulatory toxicology and safety pharmacology has already been performed. Therefore if the results of the proposed studies in mouse models of muscular dystrophy show promise, there is every prospect of rapidly moving the compound into clinical trial in patients with muscular dystrophy within 1-1.5 years of analysis of the results. As the 6 month study in the mdx mouse precedes the study in the FKRPMD mice, such a clinical trial could be initiated within 3 years of starting the grant. If the inhibition of MMP9/12 reduces the loss of muscle fibres or improves the efficiency of regeneration, then we will have a therapy that could substantially reduce the rate of disease progress and thus maintain independence for longer in a group of patients that currently lacks a therapy that maintains muscle function.