Spinal muscular atrophy (SMA) - the most common genetic cause of death in infancy - is a motor neuron disease that is caused by reduced levels of the survival motor neuron (SMN) protein and for which no effective therapy is currently available. Therefore, there is an urgent need to identify treatments that can restore SMN levels or can correct the deficits downstream of SMN depletion. SMN is an essential protein that is ubiquitously expressed and functions in RNA processing. SMA patients have homozygous loss of the SMN1 gene and retain at least one copy of the nearly identical SMN2 gene. The SMN2 gene produces low levels of the SMN protein leading to motor neuron degeneration and skeletal muscle wasting. Since higher copy numbers of the hypomorphic SMN2 gene reduce disease severity, to date most therapeutic discovery efforts for SMA have focused on increasing expression of SMN. Enhancing SMN function or correcting SMN-dependent downstream events may represent additional therapeutic avenues. However, a current limitation to the development of a treatment for SMA is the limited knowledge of suitable therapeutic targets. This research project aims to identify and characterize cellular factors that control the expression and function of the SMN protein with the ultimate goal of identifying novel avenues of therapeutic intervention for SMA. To reach this objective, we will employ a newly developed discovery platform that uses cell proliferation defects triggered by SMN deficiency as a robust phenotypic readout of functional SMN levels produced from the human SMN2 gene in NIH3T3 fibroblasts with regulated knockdown of endogenous mouse Smn. Our preliminary studies indicate that this system recapitulates, at least in part, mechanisms at play in disease.
In Aim 1, we will perform a genome-wide cDNA screen in order to identify genes whose over-expression improves the cell proliferation phenotype of Smn-deficient NIH3T3 fibroblasts. A unique advantage of the phenotypic screening strategy we propose is the potential to identify modifier genes that act on SMN biology through multiple mechanisms of action.
In Aim 2, we will use a panel of orthogonal assays to determine whether candidate modifiers revealed by the genetic screen as well as any chemical compounds known to mimic their effects i) increase SMN2 gene expression, ii) enhance SMN function, or iii) influence SMN-dependent downstream events. Importantly, we will also test the ability of these modifiers to improve survival of SMA motor neurons differentiated from mouse embryonic stem cells in order to establish their disease relevance and therapeutic potential. Collectively, our studies are designed to identify genetic modifiers of SMN expression and function as candidate targets for developing novel therapeutic approaches to SMA. They may also lead to the discovery of genes and small molecules as new research tools to study fundamental aspects of SMN biology and SMA disease mechanisms.

Public Health Relevance

Spinal muscular atrophy (SMA) is an incurable neurodegenerative disease of infancy and childhood. We will carry out a large-scale screen aimed to the discovery of genes that enhance the expression and function of the SMN protein, which is defective in SMA. Genes that will emerge from this screen may become candidate targets to develop novel therapeutic strategies for SMA. Thus, this project may have far-reaching implications for the understanding and treatment of SMA.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Molecular Neurogenetics Study Section (MNG)
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Nuckolls, Glen H
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Van Alstyne, Meaghan; Pellizzoni, Livio (2016) Advances in modeling and treating spinal muscular atrophy. Curr Opin Neurol 29:549-56