This application is in response to an NIH FOA inviting applications for projects to identify and qualify extracellular RNA (exRNA)-based biomarkers derived from human body fluids to diagnose and monitor disease progression and response to therapy. We propose to identify and validate candidate circulating miroRNAs in well-defined multiple sclerosis (MS) patient populations. Studies using existing human biospecimen collections were strongly encouraged by the NIH FOA and for the UH2 phase we will take advantage of a unique resource termed CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital). CLIMB is a cohort of over 2000 MS patients that began enrollment 12 years ago and includes yearly blood samples, clinical exams and quantitative MRI imaging. We present preliminary data that we can indeed measure circulating miRNAs in our MS cohort and have found links to disease stage, response to therapy and disability. For the UH3 phase we have identified valuable sources of blood samples from both academic and pharmaceutical collaborators that will be used to validate our UH2 findings and provide the basis for the use of circulating miRNAs in the clinic.
SPECIFIC AIMS FOR UH2 PHASE: 1) Identify miRNAs that will act as diagnostic biomarkers by comparing MS patients to healthy controls, patients with other neurological diseases and patients with other autoimmune diseases. 2) Identify disease stage miRNA biomarkers by comparing RRMS patients, SPMS patients and PPMS patients. 3) Identify prognostic miRNA biomarkers by determining the change in each miRNA over two years and assessing which miRNAs are sensitive to long-term change in disease status. 4) Identify treatment response miRNA biomarkers by comparing the baseline miRNA expression in responders and non- responders to treatment. 5) Identify disability miRNA biomarkers by correlating miRNAs with EDSS and MRI measures of disease status.
SPECIFIC AIMS FOR UH3 PHASE: Circulating miRNAs identified in the UH2 phase will be extensively studied and we will address the following two aims: 1. Validation of miRNA biomarkers identified in the UH2 phase in well defined independent patient cohorts. 2. Determine which miRNAs identified in the UH2 phase can be used as preclinical disease biomarkers. We will take advantage of well characterized serum samples from a number of sources including: The SUMMIT International MS Consortium, the NIH sponsored CombiRx clinical trial, the Biogen Idec sponsored IMPACT trial, the Swedish EIMS epidemiologic investigation of MS, the Canadian Pediatric Demyelinating Disease Study and the GEMS (Genes and Environment MS study).

Public Health Relevance

MicroRNA (miRNAs) are single stranded, small non-coding RNA molecules that regulate gene expression and protein synthesis and are involved in fundamental biological processes. MicroRNAs provide a new avenue to understand immune regulation in a disease such as MS. Moreover, circulating miRNAs have the potential to serve as biomarkers for MS.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Exploratory/Developmental Cooperative Agreement Phase II (UH3)
Project #
4UH3TR000890-03
Application #
8961481
Study Section
Special Emphasis Panel (ZRG1-GGG-R (51))
Program Officer
Tagle, Danilo A
Project Start
2013-08-01
Project End
2018-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
3
Fiscal Year
2015
Total Cost
$321,545
Indirect Cost
$140,308
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Raheja, Radhika; Regev, Keren; Healy, Brian C et al. (2018) Correlating serum micrornas and clinical parameters in amyotrophic lateral sclerosis. Muscle Nerve 58:261-269
Regev, Keren; Healy, Brian C; Paul, Anu et al. (2018) Identification of MS-specific serum miRNAs in an international multicenter study. Neurol Neuroimmunol Neuroinflamm 5:e491
Filant, Justyna; Nejad, Parham; Paul, Anu et al. (2018) Isolation of Extracellular RNA from Serum/Plasma. Methods Mol Biol 1740:43-57
Regev, Keren; Healy, Brian C; Khalid, Fariha et al. (2017) Association Between Serum MicroRNAs and Magnetic Resonance Imaging Measures of Multiple Sclerosis Severity. JAMA Neurol 74:275-285
Regev, Keren; Paul, Anu; Healy, Brian et al. (2016) Comprehensive evaluation of serum microRNAs as biomarkers in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 3:e267
Laurent, Louise C; Abdel-Mageed, Asim B; Adelson, P David et al. (2015) Meeting report: discussions and preliminary findings on extracellular RNA measurement methods from laboratories in the NIH Extracellular RNA Communication Consortium. J Extracell Vesicles 4:26533