Controlled clinical trials have established interferon beta (IFNbeta) as an important disease-modifying drug in relapsing remitting MS, leading to approval for 3 IFNbeta products. This proposal addresses important unresolved issues: 1) Therapeutic mechanisms for IFNbeta are not known; 2) There are no validated methods to quantify the response to IFNbeta in an individual patient; and 3) Biomarkers of the IFNbeta therapeutic response have not been defined. This proposal is based on the assumption that protein products of interferon-stimulated genes (ISGs) mediate clinical effects of IFNbeta in MS. The hypothesis is that induction of ISGs varies between MS patients and that the individual molecular response to IFNbeta accounts for the individual response to treatment. The primary molecular response to IFNbeta will be determined using customized cDNA macroarrays containing approximately 250 ISGs, and the response will be correlated with therapeutic response and adverse events. The macroarrays allow quantitatively assessment of ISGs in 100 patients with RR-MS who will be followed longitudinally in a prospectively designed clinical protocol. A research team with complementary expertise has been assembled to accomplish this project. The principal investigator, Dr. Richard Rudick, has substantial experience with outcomes assessment and IFNbeta studies in MS. The Co-investigator, Dr. Richard Ransohoff, has expertise in assessing molecular signalling in response to IFN and a long working collaboration with Dr. Rudick. Consultants provide expertise in statistical genetics, ISG analysis, and MRI analysis. The project is supported by preliminary data that validates the use of MRI to define response to IFNbeta in individual patients; and data demonstrating use of the customized cDNA macroarray to conduct ex vivo monitoring of IFNbeta responses in MS patients. Results will define the primary molecular responses to IFNbeta, clarify mechanisms of its clinical effects, and may elucidate pathogenic mechanisms in MS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS038667-09
Application #
7584185
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
9
Fiscal Year
2008
Total Cost
$189,486
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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