Validation of a PPMO morpholino lead compound in an animal model of FSHD

Budget

$50,000 (USD) in total, supported in partnership with Friends of FSH Research (50:50)

Lay Abstract

In a very nice review recently published in “Trends in Molecular Medicine”, Lek et al. discussed the over 10 animal models that have been developed for FSHD. That’s quite a different story than a few years ago, when there were no animal models. The purpose of these animal models is to test the efficacy of drugs that may be potentially therapeutic for FSHD. Dr. Gregory Block has written before how the nature of the drug/compound that is being tested will likely reflect which animal model we choose to use.

For example, if the lead compound targets DUX4 directly, it will suffice to simply introduce the DUX4 gene into an animal. That is what Dr. Harper has done at Nationwide Children’s Hospital in Columbus Ohio. Leveraging his expertise in adeno-associated virus (AAV) delivery of genes to skeletal muscle, Dr. Harper and team have shown that introduction of DUX4 into the muscle of mice results in the destruction of the injected muscle.

Genzyme, a biotechnology company that focuses on therapeutics for rare diseases, has developed an antisense oligonucleotide-based approach for targeting the DUX4 transcript for degradation. Make no mistake, this is not a novel approach. There are multiple projects running throughout the world looking to develop such molecules, and they are very easy to get working in cell models of disease. Where Genzyme has an advantage is in the chemistry to deliver these molecules to skeletal muscle in an animal or human. They have considerable expertise in advancing these therapeutics rapidly.

This project is one of the first that aims to test a lead compound in one of the animal models that has been developed by the community, and thus is a major milestone in the field. This model was chosen because of its simplicity. The drug can be delivered systemically, and the efficacy can be measured against a variety of concentrations of DUX4. Thus we can create a full pharmacological profile for the lead compound and understand its efficacy and toxicity in the animal model.

If this study is successful, it will pave the path for the group to aim towards larger animal studies that will generate the data needed to justify a clinical trial.

This study was co-funded by FSHD Canada.