Spinal muscular atrophy (SMA) is characterized by loss of motor neurons and atrophy of muscle. Proximal SMA is the second most common genetic cause of infant death. As in many neurogenetic disorders, the mutated protein SMN is ubiquitously expressed, yet only a particular type of neuron is affected. SMA is caused by loss of the SMN1 gene and retention of the SMN2 gene, leading to low levels of wild-type SMN, which is insufficient for motor neuron survival. Increasing SMN levels by increasing SMN2 copy number modulates the severity of the phenotype. In recent years the investigators, and others, have identified drug compounds that can induce SMN2 to produce more SMN protein. In addition, when the drug is given prior to motor neuron loss certain compounds can modify the SMA mouse phenotype. It has now become possible to perform newborn screening for SMA. However key questions remain concerning optimal deployment of therapeutics in SMA, including compounds that activate SMN2, oligonucleotides that stimulate incorporation of SMN exon7 by SMN2, or gene therapy. In this application the investigators will define the spatial and temporal requirement for high levels of SMN to correct SMA. Additionally, they will study modifiers of SMA and the effectiveness of combination drug treatments. These are essential components in order to optimize treatment regimes for SMA. In this application four aims are proposed using SMA mice. 1) Determine the importance of high levels of SMN in tissues other than neurons or motor neurons by using mouse lines that selectively create or correct the SMA condition in neurons or motor neurons. This will address if there is any benefit in SMA animals of increasing SMN levels outside the nervous system. 2) The temporal requirement for high levels of SMN to correct SMA will be determined using a SMN inducible system. This will allow determination of when SMN must be increased in SMA and whether induction of SMN must be continuous or just during a specific window of time. 3) Study the role of phosphorylation in SMN's ability to correct SMA. Additionally, they will determine if combinations of drug increase survival in SMA mice. The activity of current drugs must be increased in order to have a major impact in the SMA mouse. Combinations of drugs that activate SMN, as well as alteration of the phosphorylation state of SMN, may significantly impact the SMA phenotype. 4) Lastly, a modifier of the SMA phenotype, plastin3, has been reported. The investigators will determine if plastin3 is truly a modifier of SMA by asking whether increased plastin3 expression can correct SMA mice.
The aims proposed here will indicate the temporal spatial requirement for SMN induction, identify the optimal compound combination for induction of SMN, and indicate the importance of a reported modifier of SMA in mice. This will result in optimization of therapeutics for SMA. PROJECT NARRATIVE: Spinal muscular atrophy (SMA) is the most common genetic cause of infant death and is caused by reduced levels of the SMN protein. It is possible to perform neonatal screens to detect SMA.
The aim of this project is to determine where, when, and how to induce SMN so as to modify the SMA phenotype and develop effective treatment for SMA.

Public Health Relevance

Spinal muscular atrophy (SMA) is the most common genetic cause of infant death and is caused by reduced levels of the SMN protein. It is possible to perform neonatal screens to detect SMA. The aim of this project is to determine where, when, and how to induce SMN so as to modify the SMA phenotype and develop effective treatment for SMA.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD060586-04
Application #
8442386
Study Section
Special Emphasis Panel (ZHD1-MRG-C (07))
Program Officer
Urv, Tiina K
Project Start
2010-03-20
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$288,707
Indirect Cost
$95,920
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Mitrpant, Chalermchai; Porensky, Paul; Zhou, Haiyan et al. (2013) Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy. PLoS One 8:e62114
Porensky, Paul N; Burghes, Arthur H M (2013) Antisense oligonucleotides for the treatment of spinal muscular atrophy. Hum Gene Ther 24:489-98
Porensky, Paul N; Mitrpant, Chalermchai; McGovern, Vicki L et al. (2012) A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet 21:1625-38
Le, Thanh T; McGovern, Vicki L; Alwine, Isaac E et al. (2011) Temporal requirement for high SMN expression in SMA mice. Hum Mol Genet 20:3578-91
Burghes, Arthur H M; McGovern, Vicki L (2010) Antisense oligonucleotides and spinal muscular atrophy: skipping along. Genes Dev 24:1574-9