Genetic Modifiers of Treatment Response in DMD
Abstract
All individuals with Duchenne muscular dystrophy (DMD) share the same cause of their health problems: DNA mutations in the DMD gene on the X chromosome that lead to the inability of the gene to produce sufficient dystrophin protein in muscle tissues. In DMD, dystrophin is missing from all skeletal (limb) muscles, heart, and smooth muscles (gut and vascular tissues) from fetal life onward, but the symptoms of the disease are progressive. The progressive nature of the disease is best correlated with replacement of limb muscles with fibrofatty scar tissue; this fibrosis gradually replaces the muscle myofibers and results in muscle loss of function. While all muscles in all DMD patients share dystrophin deficiency as the cause of the disease, there is substantial variability between patients in terms of severity and response to treatments. Some patients show symptoms at a very young age, and some progress quite rapidly. Other DMD patients show a milder course. Likewise, some patients respond well to corticosteroids, gaining considerable strength with few side effects. But in other patients, they either respond poorly or show severe side effects that they are unable to tolerate treatment with corticosteroids. It may be pertinent that individual muscles within a DMD patient respond to dystrophin deficiency quite differently, with some muscle showing fibrofatty replacement at young ages, and others at much older ages. Clearly, dystrophin deficiency does not immediately cause weakness in all muscles in all patients – there is great variability. The focus of the proposed Congressionally Directed Medical Research Programs (CDMRP) Duchenne Muscular Dystrophy Research Program (DMDRP) research is to provide understanding regarding the variability in disease severity between different patients with DMD, and response to therapy. The DMD patient groups that will be studied for the proposed research are participants in the vamorolone clinical trials. These trials include 168 DMD patients in a narrow age range (4 to less than 7 years) that had not been previously treated with corticosteroids or other experimental therapies. As these were formal clinical trials for the purposes of Food and Drug Administration and European Medicines Agency drug approval, the trials were done rigorously, with extensive training and oversight of all recruitment sites and personnel. The trials were also successful, in showing that vamorolone is as effective as prednisone but is safer than corticosteroids, with no stunting of growth and potential improvements in mood disturbances typically seen with corticosteroid treatment. We will study genetic modifiers of disease severity (baseline motor function), genetic modifiers of response to therapies (corticosteroids and vamorolone). We will also carry out the first pharmacogenomics studies in DMD, where genetics of steroid drug metabolism will be compared to patient response to vamorolone and corticosteroids. It is important to note that all dystrophin replacement therapies to date introduce abnormal dystrophin on top of (add on) to corticosteroid therapy. Thus, the proposed studies will have impact even for dystrophin replacement strategies. The proposed research addresses specific aspects of the CDMRP DMDRP call for proposals. Namely: (1) Therapies addressing secondary pathologies of DMD to the extent that they augment therapies directed at primary disease mechanisms, (2) Discovery and validation of novel targets, including genetic modifiers and factors that determine the selective vulnerability/resistance of individual muscles, especially in humans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210668
Entities
People
- Eric Hoffman
Organizations
- Binghamton University
- United States Army