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

Principal Investigator: MCNALLY, ELIZABETH M
Institution Receiving Award: NORTHWESTERN UNIVERSITY
Program: DMDRP
Proposal Number: MD120051
Award Number: W81XWH-13-1-0234
Funding Mechanism: Therapeutic Idea Award
Partnering Awards:
Award Amount: $462,864.00


This proposal is designed to test a novel method to inhibit TGF-beta signaling. Transforming growth factor beta, or TGF-beta, is a major mediator of injury and scar formation in a number of chronic diseases including those that affect the kidney and lung. Increased TGF-beta signaling is a prominent feature of Duchenne muscular dystrophy (DMD), and reducing TGF-beta has been shown to improve muscle pathology and function in mouse models. Current approaches that are now being used to inhibit TGF-beta include angiotensin-converting enzymes or angiotensin receptor blockers. These agents have a limited ability to block TGF-beta because these medications act broadly throughout the body, and in doing so have dose-limiting side effects. For example, DMD patients typically have low blood pressure, especially as they get older, and these medications further lower blood pressure. Anti-TGF-beta antibodies are also being contemplated for therapy, but these antibodies may also have off target effects that limit their usefulness to treat muscle disease. We discovered a molecule that binds to TGF-beta that is highly expressed in muscle and heart called LTBP4, or latent TGF-beta binding protein 4. We also found that LTBP4 is highly expressed in injured muscle. Therefore, LTBP4 is an excellent target to block TGF-beta more specifically in dystrophic muscle and heart. The method to block TGF-beta relies on delivering an antibody against LTBP4. We have already shown that antibodies can block a hinge region of LTBP4, and the cleavage of this hinge is a necessary step for releasing and activating TGF-beta. The antibodies allow LTBP4 to remain tightly bound to TGF-beta and therefore decrease TGF-beta activity. Antibodies can be delivered long term as a therapy and are now being used commonly to treat chronic diseases such as rheumatoid arthritis and psoriasis. We propose to test antibody-based therapy in mouse models of muscular dystrophy since this is required prior to developing an antibody that can be used in humans. It is expected that the preliminary data generated in this study will provide justification for further development of a humanized antibody and ultimately clinical trials in DMD patients.