Kristen Nowak, Ph.D., Nigel Laing, Ph.D., Rhonda Taylor, Ph.D.

Nigel Laing, National Health and Medical Research Council principal research fellow and head of the Neurogenetic Disease Laboratory at the Harry Perkins Institute of Medical Research, The University of Western Australia in Perth, was awarded an MDA research grant totaling $149,412 over two years to test two potential gene therapy treatment approaches for McArdle disease.

With colleagues Kristen Nowak and Rhonda Taylor, Laing will test two potential gene therapy methods for treatment of McArdle disease in a mouse model. The work, if successful, could lead to therapies that may improve muscle function in McArdle disease.

Please describe your current research in McArdle disease.

McArdle disease occurs when an important enzyme that is required to break down energy stores in skeletal muscle is missing. The disease causes skeletal muscle pain when exercising, and in severe cases, leads to muscle weakness and wasting that can limit daily activity. There is currently no cure for McArdle disease.

We will use a mouse model of McArdle disease to test two potential gene therapy methods. Both methods will use a modified version of virus to deliver crucial genetic material. For the first method we will deliver a normal version of the missing enzyme. Although very logical, this approach is likely to cause an immune reaction as the body of a McArdle disease mouse (or a human patient) will not have seen this enzyme before.

Thus, we will also in a parallel set of experiments increase levels of an alternative version of the enzyme. This alternative enzyme is found in adult brain tissue and in fetal skeletal muscle, where it has the same function as the missing enzyme in skeletal muscles. We propose that due to this alternative brain version being so similar to the skeletal muscle enzyme, it can sufficiently restore enzyme function in the muscle if it is increased to adequate quantities. However, this version of the enzyme should not evoke an immune reaction as the body has already been exposed to it.

Theoretically the approaches being tested could be applicable to many or most patients with McArdle disease as they should not be specific to any particular gene defect. These preclinical therapeutic strategies are potentially translatable to patients if they are efficacious, and a similar approach may also be applied to other skeletal muscle diseases.

What is your focus within the McArdle disease field and why is it important?

Our focus with McArdle disease is to evaluate potential therapies for the disease, and in particular to determine whether a fetal version of the missing enzyme causing the disease can be harnessed for therapeutic use.

We believe our focus is important as there is no current cure for McArdle disease. Our approach, if efficacious, should be amenable to most/all patients with the disease, regardless of their specific gene defect/s.

What is the expected outcome of this research?

We will be evaluating how successful are two parallel gene therapy approaches for the disease. If the outcomes indicate that the disease has been treated, then our approach could theoretically be translated into clinical trials in patients. Should our results not show any positive effects on reducing the severity of disease, then this information will help direct further attempts at therapy for McArdle disease.

How will your research lead to treatments and cures?

Our study is a preclinical evaluation of two similar treatment approaches. If one or both proves efficacious in the mouse model, then this study could theoretically progress to clinical trials in patients.

What do you feel people impacted by McArdle disease can have the most hope about with respect to research right now?

We are utilizing a mouse model with exactly the same mutation as the commonest mutation in human McArdle disease. Therefore, it is very appropriate to evaluate how successful our gene therapy approaches will be in ameliorating the disease symptoms. We are using a gene therapy approach with a type of virus that has previously been shown to be safe in humans. We are optimistic that due to the missing protein being an enzyme, as opposed to a structural protein, that introducing even low levels of the missing/substitute enzyme should produce benefit as even low levels in some patients result in a mild disease.

Does your work have any potential implications for other disease fields?

Yes, the approach we are trialing is one that is applicable to other skeletal muscle diseases caused by an absence of a particular protein, in particular proteins that belong to a protein family consisting of members that have similar functions.

To learn more about how MDA research is accelerating treatments and cures for McArdle disease, please visit mda.org.