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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:
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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.
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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

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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