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Synovial Macrophage Transcriptional Signatures for Predicting Therapeutic Efficacy

Award Number: R01AR075423
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/18/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Synovial Macrophage Transcriptional Signatures for Predicting Therapeutic Efficacy - Despite the many therapies for patients with rheumatoid arthritis (RA), there is little information to guide selection of the most effective treatment for an individual patient. Forty-sixty percent of patients with RA respond (defined by ACR50 response criteria) to conventional disease modifying anti-rheumatic drugs (cDMARDs) or cDMARDs plus anti-tumor necrosis factor (TNF) therapy. Moreover, 20-40% of RA subjects in clinical trials never demonstrate even a minimal response (ACR20 response criteria). Hence, there is a clear need to develop precision-based therapy for patients with RA, whereby novel biomarkers will enhance our ability to predict therapeutic response and limit ineffective therapy. For the most part, peripheral blood has been utilized for identifying predictive biomarkers, but these studies lacked sufficient precision to allow their incorporation into clinical practice. Thus, similar to an oncologist, who identify mutations through sequencing of tumor biopsies to direct therapy, our approach is to biopsy the synovium, the target organ in RA to identify changes that reflect sensitivity or resistance to a particular therapy. We brought together six leading medical centers to create REASON, a consortium with an established framework for patient recruitment, curation of clinical data, ultrasound-guided synovial biopsies, cell sorting, RNA sequencing (RNA-seq), and computational analyses. Our data show that macrophages isolated from ultrasound-guided synovial tissue biopsies obtained from patients with RA are sufficient for RNA-seq, exhibit transcriptional differences across patients with RA, and, importantly, set the framework for the stratification of patients with RA according to the most prominent disease pathway. We are the first to identify 6 transcriptional modules of co-regulated genes from isolated synovial macrophages via ultrasound-guided synovial biopsy, that are individually associated with clinical disease status and cDMARD or biologic therapy (bDMARD). This study established REASON as a leader in the United States for ultrasound-guided synovial biopsies and demonstrates the feasibility and therapeutic potential of isolating low numbers of synovial macrophages for RNA-seq to establish a precision-medicine approach for RA therapy and to understand pathobiology. While our published study identified transcriptional signatures associated with bDMARD or methotrexate usage in RA patients with active disease, there is a central need to identify genes that are predictive of response to therapy. Our overarching hypothesis is that functional genomic analysis of synovial macrophages will identify novel transcriptional signatures that inform on response to particular therapies in individual patients, thereby enabling researchers and, ultimately, clinicians to identify the drug most likely to work for each patient.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	2/24/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $579,097 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	8/25/2023	NON-COMPETING CONTINUATION	$579,097
														Subtotal = $579,097

Issue Date FY: 2022 ( Subtotal = $570,885 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	8/8/2022	NON-COMPETING CONTINUATION	$570,885
														Subtotal = $570,885

Issue Date FY: 2021 ( Subtotal = $574,892 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/30/2021	NON-COMPETING CONTINUATION	$574,892
														Subtotal = $574,892

Issue Date FY: 2020 ( Subtotal = $669,562 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/19/2020	NON-COMPETING CONTINUATION	$600,219
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	9/7/2020	SUPPLEMENT FOR EXPANSION	$69,343
														Subtotal = $669,562

Issue Date FY: 2019 ( Subtotal = $636,545 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	9/27/2019	NEW	$0
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/18/2019	NEW	$636,545
														Subtotal = $636,545

Grand Total All Awards = $3,030,981

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Synovial Macrophage Transcriptional Signatures for Predicting Therapeutic Efficacy

Award Number: R01AR075423

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/18/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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