There have been a number of breakthroughs in the treatment of a mouse model of severe SMA in the last two years. SMA therapies that increase SMN levels in motor neurons have been most effective when delivered in the immediate postnatal period of development and they prevent the development of weakness in the mouse model. The rapid translation of these therapies to SMA patients is hampered by factors that include: 1) the paucity of natural history studies in this population, 2) the absence of qualified identifiers of biological activity of potential interventions, for example a reporter of the expression of SMN in motor neurons, and 3) the need for qualified markers of disease progression and/or markers of disease amelioration. We hypothesize, based on preclinical experiments that we have performed, that SMA clinical trials have the highest likelihood of success if therapy is initiated in a pre-clinical state. We thus propose the following specific aim in identify prognostic biomarkers and surrogate biomarkers of disease progression that will facilitate the execution of therapeutic SMA clinical trials in infants:
Aim 1 : To establish the validity of putative physiological SMA biomarkers in infants;
Aim 2 : To establish the validity of putative molecular SMA biomarkers in infants;
Aim 3 : To establish the relationship between SMN levels in motor neurons with putative physiological and molecular SMA biomarkers in infants. The successful pursuit these Aims will: 1) establish the natural history of physiological and molecular SMA biomarkers in SMA patients at the most relevant period of development, 2) establish a correlation between SMN expression levels in motor neurons with putative SMA biomarkers using a large animal model, and 3) identify markers of disease progression and determine whether changes in these markers predict motor function decline.
Spinal muscular atrophy is the leading genetic killer of infants. Strong preclinical evidence suggests that effective therapy in SMA must be delivered as early as possible to prevent progression of the disease. This project will identify prognostic biomarkers and surrogate biomarkers of disease progression that will facilitate the execution of therapeutic SMA clinical trials in infants.
| Simuni, Tanya; Caspell-Garcia, Chelsea; Coffey, Christopher S et al. (2018) Baseline prevalence and longitudinal evolution of non-motor symptoms in early Parkinson's disease: the PPMI cohort. J Neurol Neurosurg Psychiatry 89:78-88 |
| Bartlett, Amy; Kolb, Stephen J; Kingsley, Allison et al. (2018) Recruitment & retention program for the NeuroNEXT SMA Biomarker Study: Super Babies for SMA! Contemp Clin Trials Commun 11:113-119 |
| Kolb, Stephen J; Coffey, Christopher S; Yankey, Jon W et al. (2017) Natural history of infantile-onset spinal muscular atrophy. Ann Neurol 82:883-891 |
| Iyer, Chitra; Wang, Xueqian; Renusch, Samantha R et al. (2017) SMN Blood Levels in a Porcine Model of Spinal Muscular Atrophy. J Neuromuscul Dis 4:59-66 |
| Arnold, W David; Duque, Sandra; Iyer, Chitra C et al. (2016) Normalization of Patient-Identified Plasma Biomarkers in SMN?7 Mice following Postnatal SMN Restoration. PLoS One 11:e0167077 |
| Kolb, Stephen J; Coffey, Christopher S; Yankey, Jon W et al. (2016) Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Ann Clin Transl Neurol 3:132-45 |
| Arnold, W David; Sheth, Kajri A; Wier, Christopher G et al. (2015) Electrophysiological Motor Unit Number Estimation (MUNE) Measuring Compound Muscle Action Potential (CMAP) in Mouse Hindlimb Muscles. J Vis Exp : |
| Renusch, Samantha R; Harshman, Sean; Pi, Hongyang et al. (2015) Spinal Muscular Atrophy Biomarker Measurements from Blood Samples in a Clinical Trial of Valproic Acid in Ambulatory Adults. J Neuromuscul Dis 2:119-130 |
| Kolb, Stephen J; Kissel, John T (2015) Spinal Muscular Atrophy. Neurol Clin 33:831-46 |
| Duque, Sandra I; Arnold, W David; Odermatt, Philipp et al. (2015) A large animal model of spinal muscular atrophy and correction of phenotype. Ann Neurol 77:399-414 |
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