Preclinical assessment of clinic ready compounds for the treatment of Spinal Muscular Atrophy

Event Abstract Back to Event Preclinical assessment of clinic ready compounds for the treatment of Spinal Muscular Atrophy Faraz T. Farooq1, 2* 1 Emirates College for Advanced Education, Science and Mathematics Education, United Arab Emirates 2 Children's Hospital of Eastern Ontario (CHEO), Research Institute, Canada Background: Spinal muscle atrophy (SMA) is an autosomal recessive neurodegenerative disease which is characterized by the loss of α motor neurons resulting in progressive muscle atrophy (1). The loss of functional Survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene is the cause of SMA (2). Method: A potential treatment strategy for SMA is to upregulate levels of the SMN protein originating from the copy gene SMN2 which could compensate in part for the absence of the functional SMN1 gene (3-5). Goal of the study and Results: We have shown a novel therapeutic strategy for SMA treatment through the activation of the p38 and STAT5 kinase pathway activating clinic ready compounds (6, 7). Celecoxib (p38 activating drug) and Prolactin (STAT5 activator) demonstrate a clear promise for use in SMA clinical trial studies as they increase SMN protein levels, ameliorate disease phenotype in SMA mouse model, have blood brain barrier penetration and also have FDA approved status (6, 8). We have also identified other clinic ready STAT5 and p38 pathway activators as new candidates for SMA treatment (9, 10). These results provide evidence and need for FDA approved compound library screen to identify clinic ready compounds for the treatment of SMA. Conclusion: SMA is a deadly neurodegenerative disease with a prevalence of 1:10000 mostly affecting children and more than 50% affected children die before the age of two (11-16). It is the most common genetic cause of infant death and is currently untreatable (15). This study will help in the identification of clinic ready compounds as new candidates for SMA treatment which will provide us an excellent platform to extend this approach on a wider scale to other rare disorders. We believe it shall bring effective treatments closer to reality for rare genetic disorders. References References: 1. Mercuri E, Bertini E, Messina S, Solari A, D'Amico A, Angelozzi C, et al. Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy. Neurology. 2007;68(1):51-5. 2. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-65. 3. Lorson CL, Rindt H, Shababi M. Spinal muscular atrophy: mechanisms and therapeutic strategies. Human molecular genetics. 2010;19(R1):R111-8. 4. Faraz Tariq Farooq MHa, MacKenzie A. Spinal Muscular Atrophy: Classification, Diagnosis, Background, Molecular Mechanism and Development of Therapeutics. In: Kishore DU, editor. Neurodegenerative Diseases: InTech; 2013. p. 561-79. 5. Faraz Farooq AM. Current and emerging treatment options for spinal muscular atrophy. Degenerative Neurological and Neuromuscular Disease. 2015;5:75-81. 6. Farooq F, Molina FA, Hadwen J, MacKenzie D, Witherspoon L, Osmond M, et al. Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway. The Journal of clinical investigation. 2011, 121(8):3042-50. 7. Farooq F, Balabanian S, Liu X, Holcik M, MacKenzie A. p38 Mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR. Human molecular genetics. 2009;18(21):4035-45. 8. Farooq F, Abadia-Molina F, MacKenzie D, Hadwen J, Shamim F, O'Reilly S, et al. Celecoxib increases SMN and survival in a severe spinal muscular atrophy mouse model via p38 pathway activation. Hum Mol Genet. 2013;22(17):3415-24. 9. Duncan MacKenzie FS, Kevin Mongeon, Ankur Trivedi, Alex MacKenzie and Faraz Farooq. Human Growth Hormone Increases SMN Expression and Survival in Severe Spinal Muscular Atrophy Mouse Model. Journal of Neuromuscular Diseases 2014;1(1):65-74. 10. Hadwen J, MacKenzie D, Shamim F, Mongeon K, Holcik M, MacKenzie A, et al. VPAC2 receptor agonist BAY 55-9837 increases SMN protein levels and moderates disease phenotype in severe spinal muscular atrophy mouse models. Orphanet J Rare Dis. 2014;9:4. 11. Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. American Journal of Human Genetics. 2002;70(2):358-68. 12. Ogino S, Leonard DG, Rennert H, Ewens WJ, Wilson RB. Genetic risk assessment in carrier testing for spinal muscular atrophy. American Journal of Medical Genetics. 2002;110(4):301-7. 13. Ogino S, Wilson RB, Gold B. New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations. European journal of human genetics : EJHG. 2004;12(12):1015-23. 14. Pearn J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. Journal of medical genetics. 1978;15(6):409-13. 15. Roberts DF, Chavez J, Court SD. The genetic component in child mortality. Arch Dis Child. 1970;45(239):33-8. 16. Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. European journal of human genetics : EJHG. 2012 20(1):27-32. Keywords: neurodegenerative disease, Neuromuscular Disease, orphan drugs, SMA, Kinase pathway Conference: International Conference - Educational Neuroscience, Abu Dhabi, United Arab Emirates, 28 Feb - 29 Feb, 2016. Presentation Type: Poster Presentation Topic: Educational Neuroscience Citation: Farooq FT (2016). Preclinical assessment of clinic ready compounds for the treatment of Spinal Muscular Atrophy. Front. Neurosci. Conference Abstract: International Conference - Educational Neuroscience. doi: 10.3389/conf.fnins.2016.92.00008 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 10 Feb 2016; Published Online: 23 Mar 2016. * Correspondence: Dr. Faraz T Farooq, Emirates College for Advanced Education, Science and Mathematics Education, Abu Dhabi, United Arab Emirates, faraztfarooq@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Faraz T Farooq Google Faraz T Farooq Google Scholar Faraz T Farooq PubMed Faraz T Farooq Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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