Exon skipping is recognized as the most promising molecular therapeutic for Duchenne muscular dystrophy (DMD). It involves systemic delivery of anti-sense drugs targeted to 'repair'the translational reading frame of the dystrophin mRNA. The out-of-frame Duchenne mRNA is converted into an in-frame transcript capable of producing semi-functional dystrophin protein (Becker-like dystrophins). The collaborating investigators have been instrumental in development of this approach as a rational therapeutic for DMD. AVI Biopharma, with Dr. Francesco Muntoni (University College London), conducted Phase I and II studies of an exon 51 morpholino drug (up to 20 mg/kg) in DMD and demonstrated de novo dystrophin production in muscle following treatment. Pre-clinical data suggest that higher doses may be needed. Dr. Jerry Mendell (Nationwide Children's, Columbus OH) will use the same AVI drug at 30 and 50 mg/kg for up to 24 weeks to better define the therapeutic window. Fundamental to the development of these compounds is to understand the relationship between dose/regimen and renal effects, since reversible accumulation of AO in kidney has been observed at high doses in animal studies and is dose-limiting. In this Clinical Project, we propose to collect first void urine from patients in the dose-ranging trial at Nationwide Children's Hospital (Mendell) (Aim 1). This trial will be carried out in parallel to the urine biomarker discovery Project 2, and the pre-clinical therapeutic index studies carried out in Project 3.
Aim 2 of the current project is to identify biomarkers that are instructive in monitoring morpholino accumulation in the proximal renal tubule cells, and then carry out a pilot study of these markers in the DMD patient urines banked in Aim 1.
Aim 3 is to integrate data from all three projects in the specialized center for Research in Pediatric Developmental Pharmacology (RPDP) to define optimal dosing regimens for exon skipping. The proposed research project is the clinical component of the broader U54 RPDP, where we systemically investigate the therapeutic index of high dose IV morpholino drugs. The proposed research has far-reaching implications for multiple exon-specific morpholino AO drugs in DMD, including an exon 45 drug in the DoD pre-clinical effort that Dr. Connor is leading with the short term goal to facilitate an """"""""approval as a chemistry"""""""" regulatory strategy. If successful, the tools developed in this proposal could also be used to test the renal effects of other drugs.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD071601-03
Application #
8472514
Study Section
Special Emphasis Panel (ZHD1-DSR-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$134,742
Indirect Cost
$25,277
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Samardzic, Janko; Smits, Anne; Spriet, Isabel et al. (2016) Different Vancomycin Immunoassays Contribute to the Variability in Vancomycin Trough Measurements in Neonates. Biomed Res Int 2016:1974972
Shoji, Kensuke; Bradley, John S; Reed, Michael D et al. (2016) Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms. Antimicrob Agents Chemother 60:2150-6
Hathout, Yetrib; Seol, Haeri; Han, Meng Hsuan J et al. (2016) Clinical utility of serum biomarkers in Duchenne muscular dystrophy. Clin Proteomics 13:9
Samiee-Zafarghandy, S; van den Anker, J N; Laughon, M M et al. (2016) Sildenafil and retinopathy of prematurity risk in very low birth weight infants. J Perinatol 36:137-40
Allegaert, Karel; van den Anker, John N (2016) Neonatal withdrawal syndrome: reaching epidemic proportions across the globe. Arch Dis Child Fetal Neonatal Ed 101:F2-3
Allegaert, Karel; van den Anker, John N (2016) Neonatal pain management: still in search for the Holy Grail. Int J Clin Pharmacol Ther 54:514-23
Jancic, Jasna; Nikolic, Blazo; Ivancevic, Nikola et al. (2016) Multiple Sclerosis in Pediatrics: Current Concepts and Treatment Options. Neurol Ther 5:131-143
Janssen, Esther J H; Välitalo, Pyry A J; Allegaert, Karel et al. (2016) Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling. Antimicrob Agents Chemother 60:1013-21
Smits, Anne; van den Anker, John N; Allegaert, Karel (2016) Clinical pharmacology of analgosedatives in neonates: ways to improve their safe and effective use. J Pharm Pharmacol :
Hathout, Yetrib; Conklin, Laurie S; Seol, Haeri et al. (2016) Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children. Sci Rep 6:31727

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