DIA/NORD 2013 US Conference on Rare Diseases and Orphan Products: Poster Abstracts
Authors: L. Hache; A. Arrieta; T. Duong; E. Hoffman; A. Cnaan; P. Clemens; P. Kane; Robert J. Caccavale; Sheryl L. Leventhal; Annette Cartaxo; M. Speight; D. Downing; S. Pouria; J. McLaren-Howard; Katrin Bieber; M. Milz
Year: 2013

DIA/NORD 2013 US Conference on Rare Diseases and Orphan Products: Poster Abstracts The accepted Poster Abstracts for the DIA/NORD 2013 US Conference on Rare Diseases and Orphan Products: The New Era in Health Care are printed below. The posters present scientific developments related to research or studies on rare diseases or public health projects. The meeting was held October 7-9, 2013 in Bethesda, Maryland. A Novel Dissociative D9,11-Steroid, VBP15, Reduces the Increased Mucin Burden in Cystic Fibrosis Bronchial Epithelium Lindsay M. Garvin, BA, MPhil, Jennifer Peters-Hall, PhD, Kristy Brown, PhD, Amarel Saieg, MS, Tyler Jones, Yajun Chen, MD, Mary C. Rose, PhD George Washington University, Washington, DC, USA Children’s National Medical Center, Washington, DC, USA Objective: Classical glucocorticoids decrease lung inflammation and mucin expression, but have long-term side effects, which dissociative steroids minimize. The efficacy of a novel dissociative steroid (VBP15) in reducing mucin expression in cystic fibrosis (CF) and non-CF lung cells was evaluated. Method: Mucins secreted by CF and non-CF lung cell lines at homeostatic conditions were analyzed by quantitative SILAC and mass spectrometry. Cells exposed to VBP15 or Dexamethasone (Dex), or carrier control were evaluated for mucin mRNA by qRT-PCR. Secretions were analyzed for mucins by Western blot. Results: CF (DF508/DF508) (n1⁄43) and non-CF (n1⁄43) life-extended human bronchial epithelial (HBE) cell lines (Fulcher ML et al. 2009) grown at an airliquid interface (ALI) differentiated to an epithelium that morphologically mimics an airway epithelium. Prior to seeding, cells were labeled by stable isotope labeling with amino acids in cell culture (SILAC) by feeding CF cells with ‘‘heavy’’ isotopes of arginine and lysine (C6-Arg and C6, N2-Lys) and control cells with the common ‘‘light’’ arginine and lysine isotopes (C6-Arg and C6, N2-Lys). Quantitative proteomic analysis of SILAC-labeled CF and non-CF apical secretions collected from ALI cultures demonstrated increased amounts of MUC5AC (8.14 fold) and of MUC5B (4.35 fold) mucins in the CF secretome under baseline conditions (homeostasis) and in the absence of infection. These results were confirmed by Western blot analysis on 1% agarose gel electrophoresis using MUC-specific antibodies. The CF (n1⁄43) and non-CF (n1⁄43) cell lines were exposed to VBP15, Dex, or carrier control. Dex was used for the steroid exposure experiments, since our previous studies demonstrated that Dex reduces MUC5AC mRNA abundance in a doseand time-dependent manner. MUC5AC and MUC5B mRNA levels were increased in CF compared to non-CF well differentiated cells prior to steroid exposure. VBP15 and Dex reduced the mRNA abundance of MUC5AC and MUC5B in both the CF and non-CF life-extended differentiated cells and the reduction was similar for VBP15 and Dex. Strikingly, mucin mRNA in CF cells was reduced to the same levels as mucin mRNA in non-CF cells after steroid exposure. Reduction of MUC5AC and MUC5B protein levels was also observed in the apical secretions of CF and non-CF cells exposed to VBP15 or Dex. Conclusion: CF is a rare disease but the most common lethal autosomal recessive genetic disorder that affects the Caucasian population. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR), resulting in overproduction of a thick, viscous mucous in the lungs, digestive system, and reproductive tracts. Infection, inflammation and mucus overproduction in CF lungs leads to the airway obstruction that accounts for CF morbidity and mortality. Drugs that have the potential to relieve the mucin burden in CF lungs could reduce morbidity and mortality. Traditional glucocorticoids are anti-inflammatory steroids; however, adverse side effects result from their long-term use. These side effects are mediated through direct binding of ligand activated-glucocorticoid receptor (GR) to glucocorticoid responsive elements (GRE) on the promoter region of GR-targeted genes. VBP15, a novel dissociative D9,11-steroid, lacks GRE-mediated transactivation activities but maintains the anti-inflammatory efficacy of traditional steroids through NFkB inhibition and GR translocation. Steroids are not standard therapy for CF patients due to potential induction of diabetes and reduced growth among other adverse side effects; however, steroid therapy is often unavoidable in many CF individuals due to frequent exacerbations. Our data show that MUC5AC and MUC5B, the predominant mucins in lung secretions, are increased at the mRNA and protein levels in CF compared to non-CF HBE cells and that both VBP15 and Dex reduce mucin gene expression in CF and non-CF HBE cells, suggesting that steroids could be effective anti-mucin agents in CF. This data suggests that VBP15, which has anti-inflammatory and mow demonstrated anti-mucin properties, may be useful in treating or preventing the increased mucin burden in CF lungs without the adverse side effects seen with other steroids. Therapeutic Innovation & Regulatory Science 47(6) 723-740 a DIA 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/2168479013505835 tirs.sagepub.com The Cooperative International Neuromuscular Research Group (CINRG) Is a Successful Network for Neuromuscular Research Lauren P. Hache, MS, CGC, Adrienne Arrieta, MS, Tina Duong, MPT, Eric Hoffman, PhD Avital Cnaan, PhD, Paula R. Clemens, MD Children’s National Medical Center, Washington, DC, USA University of Pittsburgh, Pittsburgh, PA, USA Department of Veterans Affairs Medical Center, Pittsburgh, PA, USA Objective: The Cooperative International Neuromuscular Research Group (CINRG) is a consortium of academic and research centers who pursue multi-center clinical research with a goal to positively impact the lives of neuromuscular disease patients and their families. Method: The CINRG network was established in 2000 and is comprised of a Coordinating Center and over 25 sites from around the world to perform clinical studies in neuromuscular disorders. The network is governed by an Executive Committee with By-Laws and Standard Operating Procedures. Results: An external Scientific Advisory Committee guides CINRG on issues that impact scientific direction and the CINRG Data and Safety Monitoring Board supports CINRG to assure participant safety and data integrity. CINRG subcommittees provide expertise for the selection of outcomes and potential therapeutics to be studied by the network. CINRG has conducted 18 studies including tests of safety and efficacy of new and repurposed drugs. CINRG has expertise in the conduct of natural history studies. The focus of CINRG studies includes numerous different muscular dystrophies: Duchenne, Becker, limb girdle and facioscapulohumeral muscular dystrophy. CINRG currently conducts the largest and longest natural history study ever done in Duchenne with 340 patients enrolled and additional funding secured to enroll 100 young Duchenne participants. Participants have been followed for over six years. CINRG has been a pioneer in the advancement of study outcomes through the development and validation of endpoint measures. CINRG has developed a standardized testing system called the CINRG Quantitative Measurement System (CQMS). CQMS integrates a novel method to measure strength, anthropometry, pulmonary function, and timed function with direct data entry to increase accuracy and efficiency. Study execution is streamlined through central procedures that include the execution of a master agreement with all participating sites. This umbrella agreement covers overall participation in the network and provides the legal structure to which study-specific agreements are addended. All centers are provided with centralized training for protocol execution and outcome measures. Regulatory documentation is centrally tracked through specialized software that facilitates collection and tracking of documents and seamlessly stored in one system that links all sites and studies. CINRG utilizes OpenClinica software that is 21 CRF Part 11 compliant and ensures data security, accuracy, reporting and storage. Handling of data requests and review of presentations and publications is managed by the CINRG Publications Subcommittee. Over the past 12 months this subcommittee has reviewed over 30 requests that include abstracts, presentations, manuscripts, and data requests. Conclusion: In the last decade CINRG has completed eleven clinical studies. This has led to the CINRG network gaining expertise in many areas of neuromuscular clinical research: grant preparation, study design and protocol creation, form/database design and creation, project management, regulatory, monitoring, data management, biostatistics, and clinical evaluation outcomes measure selection and management. The CINRG Duchenne Natural History Study shows the strength of the CINRG network. The data are already proving to serve as a resource to the Duchenne community for planning trials and better understanding disease. CINRG has become an invaluable resource within and outside of its network for data analyses. The CQMS has been shown to be a useful outcome measurement system with proven reliability testing across all studies and sites. CINRG has positively impacted the lives of neuromuscular patients and families by conducting well-controlled clinical studies that greatly contribute to a better understanding of neuromuscular diseases. Membrane Stabilization With Phospholipids for Lipid Storage Disorders Patricia C. Kane, PhD, Robert J. Caccavale, MD, Sheryl L. Leventhal, MD, Annette L. Cartaxo, MD, Mark O’Neal Speight, MD, Damien Downing, MD, Shideh Pouria, MD, John McLaren-Howard, PhD, Katrin Bieber, MD, Meinrad Milz, MD NeuroLipid Research Foundation, Millville, NJ, USA UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA Private Practice, Valley Cottage, NY, USA Newton Memorial Hospital, Newton, New Jersey; Mor