Although great promise has been shown for therapy of muscular dystrophy by gene and stem cell therapies, and steroids appear to improve physiological function, the complexity of the total disease process and the rapid progression to death in these patients begs for practical alternative strategies. The purpose of this proposal is to develop and evaluate new approaches to multiplexed therapeutics of muscular dystrophy based on recent progress in our laboratory that may bring targeted nanosystems to bear on diagnosis, therapy, and image-based management of muscular dystrophy. In this translational proposal, all of the required synthetic and analytical tools are at our disposal to conclusively determine if a targeted nanotechnology platform adds value to the management of experimental models of muscular dystrophy, which is a proposition that heretofore has never been tested. The overarching hypothesis of this proposal is that: nanotechnology-based approaches add unique and valuable assets to the diagnostic and therapeutic armamentarium in neuromuscular disorders, and will contribute in a directly translational way to the clinical management of neuromuscular disorders. The deliverables, or outcomes, envisioned in the specific aims and outlined in the experimental plan are: 1) Formulation of nanoparticles targeted to inflammatory biomarkers of disease to noninvasively, sensitively, and accurately report the activity and the evolution of the muscular dystrophy disease process through image- based readouts of selected molecular biomarkers of pathophysiological significance to the early inflammatory changes that contribute to the deterioration of cardiac and skeletal muscle;2) Development of novel methods for repeated delivery of potent drugs and genetic materials to targeted sites of inflammation with reduced toxicity profiles as compared with current therapeutic approaches;and 3) Integration of image-based readouts of disease activity in conjunction with therapeutic delivery to allow rational adjustment of agents and dosing, and establishment of clinical follow-up strategies to facilitate "individualized" clinical management.

Public Health Relevance

Although great promise has been shown for therapy of muscular dystrophy by gene and stem cell therapies, and steroids appear to improve physiological function, the complexity of the total disease process and the rapid progression to death in these patients begs for practical alternative strategies. The purpose of this proposal is to develop and evaluate new approaches to multiplexed therapeutics of muscular dystrophy based on recent progress in our laboratory that may bring targeted nanosystems to bear on diagnosis, therapy, and image- based management of muscular dystrophy. In this translational proposal, all of the required synthetic and analytical tools are at our disposal to conclusively determine if a targeted nanotechnology platform adds value to the management of experimental models of muscular dystrophy, which is a proposition that heretofore has never been tested.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056223-05
Application #
8485545
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (02))
Program Officer
Nuckolls, Glen H
Project Start
2009-09-28
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$308,785
Indirect Cost
$105,637
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Zhou, Hui-fang; Yan, Huimin; Pan, Hua et al. (2014) Peptide-siRNA nanocomplexes targeting NF-?B subunit p65 suppress nascent experimental arthritis. J Clin Invest 124:4363-74
Bibee, Kristin P; Cheng, Ya-Jian; Ching, James K et al. (2014) Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function. FASEB J 28:2047-61
Zhang, Lei; Allen, John; Hu, Lingzhi et al. (2013) Cardiomyocyte architectural plasticity in fetal, neonatal, and adult pig hearts delineated with diffusion tensor MRI. Am J Physiol Heart Circ Physiol 304:H246-52
Hou, Kirk K; Pan, Hua; Ratner, Lee et al. (2013) Mechanisms of nanoparticle-mediated siRNA transfection by melittin-derived peptides. ACS Nano 7:8605-15
Li-Byarlay, Hongmei; Li, Yang; Stroud, Hume et al. (2013) RNA interference knockdown of DNA methyl-transferase 3 affects gene alternative splicing in the honey bee. Proc Natl Acad Sci U S A 110:12750-5
Hou, Kirk K; Pan, Hua; Lanza, Gregory M et al. (2013) Melittin derived peptides for nanoparticle based siRNA transfection. Biomaterials 34:3110-9
Hughes, M S; McCarthy, J E; Marsh, J N et al. (2013) Joint entropy of continuously differentiable ultrasonic waveforms. J Acoust Soc Am 133:283-300
Pan, Hua; Ivashyna, Olena; Sinha, Bhaswati et al. (2011) Post-formulation peptide drug loading of nanostructures for metered control of NF-ýýB signaling. Biomaterials 32:231-8