Duchenne Muscular Dystrophy (DMD) is the most frequent of all lethal X linked recessive disorders occurringin 1 of 3,500 boys. The disease results from the degeneration of skeletal and heart muscle as aconsequence of mutations in the dystrophin gene. Typically, DMD boys have difficulty walking at an earlyage, become wheelchair dependent by their teen years, and die by their late 20s or early 30s. Sadly,treatment options are limited and effective therapies to curb muscle wasting and extend patient survivalremains elusive. In this proposal we demonstrate that the use of a specific NFkB inhibitor compound canprovide both a histological and functional improvement to skeletal muscles of mdx mice. The inhibitor is an11 amino acid peptide, referred to as NBD, which functions by blocking the assembly of the IKK complexrequired for NFkB activation in response to stimuli. Treatment with NBD in young mdx mice prior to the onsetof necrosis reduces macrophage infiltration and prevents myofiber lysis. Significantly, treatment of mice evenin a post-necrotic phase reduces inflammation, and in addition stimulates new fiber formation. Furthermore,as described in other chronic injury models, no associated toxicity was found with NBD treatment. Togetherthese data provide pre-clinical efficacy data that supports the use of a specific NFkB inhibitor compound forthe treatment of DMD. The data further suggests that the IKK/NFkB signaling pathway is a valid therapeutictarget. Indeed, we find that NFkB transcriptional activity is chronically elevated in multiple dystrophicmuscles. Genetic ablation of either the transcriptionally competent p65 subunit of NFkB or the IKKbetasubunit, that is sensitive to NBD treatment, modulated the immune response and increased myogenesis inmdx mice. Based on these data, we propose that chronic activation IKK/NFkB signaling contributes to DMDpathology by functioning in both immune cells to promote necrosis and in skeletal muscle fibers to inhibitregeneration. The purpose of this proposal is to determine whether NBD treatment is efficacious in clinicallyrelevant models of DMD. To make this determination we will perform Phase I and II pre-clinical trials usingdystrophin-deficient murine and dog models of this disease. If milestones are achieved, safety studies willfollow to support an IND application. Results obtained from this proposal may lead to the development of anew treatment option to improve the quality of life and/or survival of DMD patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
United States
Zip Code
Peterson, Jennifer M; Wang, David J; Shettigar, Vikram et al. (2018) NF-?B inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model. Nat Commun 9:3431
Tilstra, Jeremy S; Gaddy, Daniel F; Zhao, Jing et al. (2014) Pharmacologic IKK/NF-?B inhibition causes antigen presenting cells to undergo TNF? dependent ROS-mediated programmed cell death. Sci Rep 4:3631
Chen, Qian; Liu, Kai; Robinson, Andria R et al. (2013) DNA damage drives accelerated bone aging via an NF-?B-dependent mechanism. J Bone Miner Res 28:1214-28
Yang, Chenjie; Ruffner, Melanie A; Kim, Seon-Hee et al. (2012) Plasma-derived MHC class II+ exosomes from tumor-bearing mice suppress tumor antigen-specific immune responses. Eur J Immunol 42:1778-84
Yang, Chenjie; Chalasani, Geetha; Ng, Yue-Harn et al. (2012) Exosomes released from Mycoplasma infected tumor cells activate inhibitory B cells. PLoS One 7:e36138
Malik, Vinod; Rodino-Klapac, Louise R; Mendell, Jerry R (2012) Emerging drugs for Duchenne muscular dystrophy. Expert Opin Emerg Drugs 17:261-77
Peterson, Jennifer M; Bakkar, Nadine; Guttridge, Denis C (2011) NF-ýýB signaling in skeletal muscle health and disease. Curr Top Dev Biol 96:85-119
Niedernhofer, Laura J; Glorioso, Joseph C; Robbins, Paul D (2011) Dedifferentiation rescues senescence of progeria cells but only while pluripotent. Stem Cell Res Ther 2:28
Reay, Daniel P; Yang, Michele; Watchko, Jon F et al. (2011) Systemic delivery of NEMO binding domain/IKK? inhibitory peptide to young mdx mice improves dystrophic skeletal muscle histopathology. Neurobiol Dis 43:598-608
Delfín, Dawn A; Xu, Ying; Peterson, Jennifer M et al. (2011) Improvement of cardiac contractile function by peptide-based inhibition of NF-?B in the utrophin/dystrophin-deficient murine model of muscular dystrophy. J Transl Med 9:68

Showing the most recent 10 out of 13 publications