Preclinical Testing of a Novel Method to Block TGFbeta Family Proteins in DMD

Posted September 7, 2017

Elizabeth McNally, M.D., Ph.D., Northwestern University

Duchenne Muscular Dystrophy (DMD) is a devastating form of muscular dystrophy, and it is estimated that 20,000 individuals in the United States have DMD. There is great promise for new Duchenne therapies right now, with the first approval of a drug that begins to treat the underlying problem, loss of dystrophin. However, new approved therapies are useful in less than 15% of DMD patients because they are for specific gene mutations. In addition, the new drugs are only partly effective, so additional approaches are needed. Dr. Elizabeth McNally and colleagues used genetic data to identify pathways that naturally modify the outcome of muscular dystrophy in animal models. They discovered that a gene, called Latent TGFβ Binding Protein-4 (LTBP4), can modify the outcome, making it better or worse, depending on the gene signature. LTBP4 can stabilize the plasma membrane and reduce fibrosis through its ability to sequester TGFβ, a mediator of tissue injury and repair. Based on this LTBP4 has been pursued as a potential therapeutic target.

Left to Right: David Barefield, Ph.D., Elizabeth McNally, M.D., Ph.D.

Left to Right: Mattia Quattrocelli, Ph.D.
Elizabeth McNally, M.D., Ph.D., Joyce Ohiri

Dr. McNally used this genetic information to design antibodies to block part of the activity of LTBP4 (figure below) and with support from a Duchenne Muscular Dystrophy Research Program FY12 Therapeutic Idea Award her team conducted various preclinical studies with these antibodies to determine whether blocking proteolysis is an effective way to stabilize muscle and reduce fibrosis. This was a unique approach to finding new pathways to treat DMD. What is exciting is that Dr. McNally originally discovered LTBP4 in mouse models, but it also works in humans with DMD as a modifier. She is now working with Solid Bioscience in Cambridge, MA, to develop better antibodies that will work in humans and with greater affinity. This approach, looking for modifiers, was very novel when Dr. McNally first started it. This is the type of science that is not likely to be undertaken in industry or in the pharmaceutical companies because it is considered too high-risk.

The left panel shows muscle stained with an anti-LTBP4 antibody (green). LTBP4 is seen on the surface of individual muscle fibers in a striated (striped) pattern and is also enriched between individual fibers. The right panel shows the strategy to block release of TGFβ, a mediator of muscle pathology both in muscle injury and in chronic muscle disease like DMD.


(1) Ceco E, Bogdanovich S, Gardner B, Miller T, DeJesus A, Earley JU, Hadhazy M, Smith LR, Barton ER, Molkentin JD and McNally EM. 2014. Targeting latent TGFbeta release in muscular dystrophy. Science Translational Medicine 6:259ra144. PMC4337885


Public and Technical Abstracts: Preclinical Testing of a Novel Method to Block TGFbeta Family Proteins in DMD

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Last updated Thursday, May 26, 2022