AMP RA/SLE Program Overview
The National Institutes of Health (NIH), pharmaceutical companies and nonprofit organizations have together created the Accelerating Medicines Partnership (AMP) to develop new ways of identifying and validating promising biological targets for diagnostics and drug development. A major goal is to generate pre-competitive, disease-specific data that will be publicly accessible to the broad biomedical community for further research (https://www.nih.gov/science/amp/).
The partners have designed a project plan to address relevant challenges for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) through the AMP RA/SLE Program. The goal is to ascertain and define shared and disease-specific biological pathways in order to identify relevant drug targets for the treatment of autoimmune diseases. This program fosters an enhanced systems-level understanding of gene expression and signaling in target tissues from affected end organs (synovium for RA, kidney and skin for lupus) and blood cells. The initial focus of research will be on RA and lupus, with the flexibility to expand in the future to related autoimmune diseases contingent on scientific feasibility and availability of resources.
AMP RA/SLE Program Research Phases
In September 2014, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institute of Allergy and Infectious Diseases (NIAID), as participating members of the AMP RA/SLE Program, funded a collaborative AMP RA/Lupus Network composed of sites across the United States. The Network was developed by NIH in collaboration with industry partners that are co-funding and actively participating in guiding the Network’s scientific direction. The individual projects within the Network are progressing along a predetermined set of steps to ensure standardization of procedures and minimize technical variability.
In March 2016, the AMP RA/Lupus Network successfully completed Research Phase 0 (standard operating procedures development and validation) and launched Phase I studies. Sample collection for the Phase I studies has ended, and quality control assessments of Phase I data are expected to be completed in 2017. Phase II is currently underway. Additional information about the Research Phases and the Network’s accomplishments is provided below.
Research Phase 0
Highlights of the Network’s Phase 0 work include the following:
- Established Network infrastructure for communications and decision-making, as well as policies to allow for timely sharing of data.
- Tested different means of obtaining and prepping tissue and, based on the results, developed standard operating procedures for preparation of synovial (joint) tissue for RA projects and kidney tissue for lupus projects.
- Tested and validated cutting-edge technologies, such as CyTOF (Cytometry by Time of Flight) and RNA-seq (RNA sequencing), in synovial and kidney tissues.
- Developed proposals for pilot projects to explore other emerging technologies and additional types of biological specimens.
- Established clinical protocols and procedures for Phase I studies.
- Established systems for data management and analysis, including databases for clinical data and biospecimen tracking, and storage of experimental data.
The Phase 0 standard operating procedures that were developed by the Network allow cross-tissue comparisons that would not otherwise be possible. These procedures are anticipated to be widely applicable to studies of human disease tissues and, already, the AMP RA/SLE initiative is serving as a demonstration of state-of-the-art analysis of human disease tissues.
Research Phase I
In Phase I, the Network used the standardized technologies established in Phase 0 to analyze samples from patients with RA and SLE. Research Phase I also included analysis of samples from individuals without RA or SLE, using a systems biology approach to identify pathways that distinguish disease and non-disease tissue:
- SLE Phase I study: The Network conducted a multi-center study in SLE patients with active renal disease requiring biopsy. Researchers compared the RNA-seq signature of kidney biopsies from SLE patients and living donors (controls). They also performed single-cell RNA-seq on paired urine and skin samples from lupus patients, and used CyTOF to analyze paired blood from lupus patients and control participants.
- RA Phase I study: The Network conducted a multi-center study in RA patients and a comparison group of osteoarthritis (OA) patients. The RA researchers also established a program in the United States to obtain synovial biopsies using minimally invasive ultrasound-guided technology to enhance capacity for tissue acquisition for the AMP RA projects. The Phase I study compared RNA-seq and CyTOF signatures of RA and OA arthroplasties and biopsies. In addition, paired blood samples were analyzed by CyTOF.
- The Network successfully completed sample accrual for Phase I studies in RA and SLE.
- Investigators demonstrated the feasibility of the AMP methods for tissue and cell collection and processing, as well as for data analysis. Researchers are able to distinguish disease and control tissues using various technologies, and identify cell populations in tissue samples that may be relevant to pathological processes.
The Phase I results have been used to inform the feasibility and design of larger studies to be carried out during Phase II. Phase I progress was discussed at the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council meeting on June 21, 2017. (The Council meeting can be viewed here. The AMP presentation begins at 03:08:28.)
Research Phase II
Phase II studies will be conducted with a larger number of patients. To improve understanding of disease heterogeneity, subgroups of patients will be compared within a disease, e.g., RA: early vs. established RA, comparison among disease-modifying anti-rheumatic drug (DMARD)-treated groups; lupus: comparison among classes of kidney disease.
- SLE Phase II study: Plans have been developed for a prospective multi-center longitudinal study of lupus patients with active renal disease who require a biopsy.
- RA Phase II study: Plans have been developed for a prospective multi-center longitudinal study, using biopsies and arthroplasty tissue, of RA patients across the spectrum of disease from DMARD naïve to end-stage disease.
- Researchers will continue to improve tissue processing and analytic methodologies.
- RNA-seq and CyTOF will continue to be the main technologies used to process tissue samples; however, use of potential emerging new technologies is being explored.