Blocking Fibroadipogenic Progenitor Response to Fibrotic Stiffness to Enhance Efficacy of Microdystrophin Gene Therapy
Abstract
The buildup of scar tissue, also known as fibrosis, is a dominant feature of muscles in Duchenne muscular dystrophy (DMD). DMD is caused by loss of expression and function of the gene dystrophin. Gene therapies that restore functional dystrophin expression and thus improve muscle function are now in clinical trials. However, when gene therapy is delivered to a muscle that already has significant scar tissue, the effectiveness of therapy can be diminished. Scar tissue in muscle is created by fibrogenic cells that can help support recovery from injury, but in the case of DMD, produce excessive scar tissue formation in the muscle and decline in muscle function. The pathologic stiffness of muscles in DMD is a critical factor in both the activation and sustaining of the expanding fibrogenic cells. Our goal is to determine if muscle scar tissue indeed limits the efficacy of dystrophin gene therapies. If so, targeting the fibrogenic cells specifically will likely enhance the environment for more successful treatment of DMD. DMD has long been a target of gene therapy. Gene therapies have been in development that replace dystrophin function with a miniaturized size of the gene that can be effectively delivered systemically to the body. While many results are promising, studies largely initiate treatment early, before the onset of severe scar tissue buildup and dramatic functional decline. Early evidence suggests a decline in therapeutic efficacy as subjects age and develop more scar tissue. Thus, our first objective is to establish the relationship between scar tissue and efficacy of dystrophin gene therapy. Therapies that block formation of scar tissue have been attempted in muscle extensively but have largely been disappointing due to side effects of blocking wound repair and healing processes. Scar tissue is made up primarily of collagen that creates an extensively stiff environment. The stiff environment directs cells into converting into fibrogenic scar producing cells. A stiff environment also causes those fibrogenic cells to ignore cell death signals that clear collagen-producing cells in healthy tissue after their function in wound healing is served. Fortunately, therapeutics with the ability to disrupt cell sensing of stiffness to either prevent both the conversion to fibrogenic cells or restore cell death susceptibility have been discovered. Our second objective is to establish if limiting the response to stiffness is able to reduce scar tissue formation and enhance the benefit of dystrophin gene therapy. While gene therapy and miniaturized dystrophin have been studied extensively and are advancing in clinical trials currently, little is known regarding how the tissue environment will impact the efficacy of these therapies. Scar tissue is known to limit muscle repair, and preventing scarring has long been a target in DMD, with efforts aimed at blocking collagen production. Alternatively, our approach focuses on blocking cellular sensing of stiffness, which has the potential to leave other important collagen functions intact. The investigation of two drugs that have not been examined in DMD but show potential to specifically target stiffness causing activation of fibrogenic cells response or inducing their cell death could augment the efficacy of gene therapy in patients with established fibrosis. Early clinical trials, along with mouse studies show reduction in benefit from gene therapy as subjects age and muscles become more fibrotic. One potential benefit of this study is to classify patients based upon the level of scar tissue to deliver gene therapy to patients where it will be most impactful. This is significant, with the limited availability of gene therapy and the possibility gene therapy could only be applied once in a lifetime. Critically, this work has the potential to expand the reach of these promising gene therapies with a pre-treatment regimen to reduce scaring and prime the m
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211058
Entities
People
- Lucas R Smith
Organizations
- United States Army
- University of California, Davis