September 17, 2019 / Research

PPMD Awards University of Florida $1 Million for Novel Gene Therapy Approach Targeting the Heart

As you know, one of PPMD’s priorities in the fight to end Duchenne is maintaining cardiac health and preventing heart disease or dilated cardiomyopathy (DCM), better known as heart failure in Duchenne muscular dystrophy. Heart issues don’t just affect some people with Duchenne; they affect ALL people with Duchenne. And while we have improved cardiac care in Duchenne, we still need treatments that repair our children’s hearts. Selfishly, I have been asking questions for a very long time.  Chris and Patrick died of heart failure and the heart is at the center of Duchenne for me and for PPMD.

That’s why I am extremely proud to announce that as part of our ongoing Cardiac Initiative, PPMD has committed to funding $1 million to H. Lee Sweeney, PhD and his team at the University of Florida (Gainesville) to continue their exploration of developing novel therapies that can address the causes of dilated heart failure in Duchenne and Becker. This $1 million investment is a direct result of this community’s generosity during our 2018 end of the year campaign and the support of other Duchenne families and foundations, including the Killian Family, Team Joseph, Kindness Over Muscular Dystrophy, Another Day for Gray Foundation, and Small Heroes Foundation.

Gene therapy, utilizing AAV vector as the delivery vehicle, provides a potential strategy to deliver transgenes targeting the mechanisms underlying the development of dilated cardiomyopathy. This funding supports the development of a heart specific therapy using an AAV vector containing two transgenes to restore calcium handling and prevent mitochondrial dysfunction. This therapy will potentially be able to treat the hearts of people living with Duchenne and Becker, in a way that is independent of, or complementary to, micro-dystrophin based gene therapy.

This is what Dr. Sweeney and his team are exploring and why PPMD was eager to provide such significant support at this critical moment.

“These are exciting times for gene therapies – especially for gene therapies for Duchenne and Becker muscular dystrophy. However, while the current therapies may potentially help the skeletal muscles of patients, there is more to learn and to develop before we can be confident that we are doing all we can for the hearts of patients. The funds provided by PPMD will allow us to move faster toward the goal of creating the best possible gene therapy for the hearts of people with Duchenne and Becker.”

– H. Lee Sweeney, PhD

Duchenne & the Heart

Understanding the effects of Duchenne on the heart is complicated and has been evolving for some time. Long ago, I asked what we know or needed to know about heart failure:

  • When does it start?
  • How will we know? What tests are appropriate?
  • Are we able to predict progression in heart failure?

Back then these questions were dismissed, clinicians suggesting that heart failure occurs in adults, not young people and the onset is sudden, not a slow gradual build which we believe is the case. For the last 15 years, PPMD has been asking those basic questions. And we knew that in order to get answers, we needed to support understanding and characterizing heart disease in Duchenne, explore the use of existing medications to impact the heart, and fund the development of novel interventions.

Understanding Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is the most common type of human cardiomyopathy, occurring mostly in adults 20 to 60. It affects the heart’s ventricles and atria, the lower and upper chambers of the heart, respectively. Most forms of DCM are acquired forms from a number of causes that include coronary heart disease, heart attack, high blood pressure, diabetes, thyroid disease, viral hepatitis, and viral infections that inflame the heart muscle. In the case of certain forms of Becker, as well as in most cases of Duchenne, cardiomyopathy can ultimately limit the patient’s survival.

While cardiomyopathy associated with Duchenne is technically a dilated cardiomyopathy that progresses to heart failure, many clinicians don’t consider it a typical DCM because the patients’ hearts don’t tend to dilate until rather late in the disease progression. However, this is likely due to the fact that the hearts are not significantly burdened because of the patients’ skeletal muscle disease and lack of ability to exercise.

Although Duchenne hearts do not dilate until late in disease progression, they get progressively stiff at earlier time points. This is clearly due to progressive fibrosis, and is slowed by the use of anti-fibrotic drugs, such as ACE inhibitors or ARBs (Angiotensin II Receptor Blockers). Interestingly, because of the fibrosis and lack of burden on the heart, the left ventricular chamber is actually smaller in diameter than normal after age 8 and until late in disease progression, when it begins to dilate.  Again, consistent with this being related to the fibrosis is the fact the individuals who were not given ACE inhibitors early in disease progression show the smallest ventricular diameters and progress the fastest once they begin to dilate.

In the case of Becker, there clearly is a subset of Becker patients that show a disproportionately rapid progression of their cardiac disease as compared to their skeletal muscle disease. This has called attention to the fact that there are some regions of the dystrophin molecule that are more important in the heart than they are in skeletal muscle, likely because of components that differ in importance or even in identity between the heart and skeletal muscle.

What Have We Learned from Our Investments Over Time?

We have learned so much since 1994, however there is still so much to learn. To better understand what we have learned from our ongoing cardiac investments thus far, click here.

Thank you again to everyone who has supported both our Cardiac Initiative and our Gene Therapy Initiative over the years. Ending Duchenne means attacking the disease with multiple approaches from multiple angles and with your support we will continue to not only explore the most promising treatments, we will do it while protecting the hearts and muscles of our loved ones.

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