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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS079163-03
Application #
8708229
Study Section
Special Emphasis Panel (ZNS1-SRB-G (54))
Program Officer
Moy, Claudia S
Project Start
2012-08-15
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$546,389
Indirect Cost
$134,251
Name
Ohio State University
Department
Neurology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Arnold, W David; Burghes, Arthur H M (2013) Spinal muscular atrophy: development and implementation of potential treatments. Ann Neurol 74:348-62