Accelerating Medicines Partnership: Organizational Structure and Preliminary Data From the Phase 1 Studies of Lupus Nephritis

Hoover, Paul; Der, Evan; Berthier, Céline C.; Arazi, Arnon; Lederer, James A.; James, Judith A.; Buyon, Jill P.; Petri, Michelle; Belmont, H. Michael; Izmirly, Peter; Wofsy, David; Hacohen, Nir; Diamond, Betty; Putterman, Chaim; Davidson, Anne

doi:10.1002/acr.24066

Cited by 21 publications

(17 citation statements)

References 42 publications

(54 reference statements)

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“…In this study, we present extensive transcriptional and clonotypic changes in lupus-prone mice, which may serve as a resource for ongoing profiling of SLE (165,166). Characterization of novel myeloid subsets, CD8 metabolism, and MZ B cell loss highlights disease mechanisms for potential therapeutic targeting.…”

Section: Discussionmentioning

confidence: 99%

Lupus Susceptibility Loci Predispose Mice to Clonal Lymphocytic Responses and Myeloid Expansion

Akama-Garren

Carroll

2022

The Journal of Immunology

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to generate a single-cell dataset of a spontaneous mouse model of lupus. Singlecell sequencing captured vast changes in immune cell heterogeneity and phenotype, including identification of novel myeloid subpopulations associated with lupus. Metabolic modeling revealed opposing changes in metabolic activity between B cells and myeloid cells in lupus-prone mice. BCR tracing identified clonal expansion toward the plasma cell (PC) compartment, and algorithmic analyses of the TCR repertoire were capable of separating CD4 clonotypes based on genotype. Ligandreceptor interaction analysis highlighted signaling relationships between innate and adaptive immune cell types that may contribute to loss of tolerance.Functional validation using coculture experiments demonstrated decreased ability of autoimmune splenocytes to stimulate Ag-specific CD4 responses. As the first single-cell atlas of lupus-prone mice to our knowledge, our dataset serves as a resource for therapeutic target discovery and biological characterization of autoantibody-mediated disease. Materials and Methods MiceC57BL/6J (B6, JAX no. 000664), B6.SJL (CD45.1, JAX no. 002014), and SLE.yaa mice (JAX no. 021569) were obtained from The Jackson Laboratory. OT-II mice were a gift from Gabriel Victora (Rockefeller University) and crossed onto a CD45.1 background. Mice were maintained at Harvard Medical School in an American Association for the Accreditation of Laboratory Animal Careaccredited facility. Fifteen-week-old male mice were used for all experiments unless noted otherwise. All animal experiments were approved by the Institutional Animal Care and Use Committee of Harvard Medical School (IS111). ImmunizationImmunization was performed by i.p. injection of 100 mg of 4-hydroxy-3nitrophenyl acetyl hapten conjugated to OVA (NP-OVA, Biosearch Technologies) in 50 ml of HBSS emulsified with 50 ml of Imject alum adjuvant (Thermo Scientific). Three weeks after immunization, mice were boosted with i.p. 100 mg NP-OVA in 100 ml of HBSS (Corning Life Sciences). Mice were sacrificed 10 d after booster immunization.

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Section: Discussionmentioning

confidence: 99%

Lupus Susceptibility Loci Predispose Mice to Clonal Lymphocytic Responses and Myeloid Expansion

Akama-Garren

Carroll

2022

The Journal of Immunology

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“…To examine the commonality of immune marker gene expression and their potential utility in other glomerular diseases, we evaluated their expression in the immune single cell data from the lupus nephritis subjects in the Accelerating Medicines Partnership (AMP), 21 as reported by Arazi et al 22 We observed that the top 16 immune marker genes from FSGS monocytes and lymphocytes were also highly expressed in the monocyte and lymphocyte clusters, respectively from lupus nephritis subjects (Figures 6A-B). We also evaluated the expression of these immune genes in the bulk RNA-seq data of urine samples from another multi-ethnic cohort of lupus nephritis subjects and found that subjects with active disease (defined as urine protein: creatinine ratio > 0.5) had higher expression of these genes than those with inactive disease (urine protein: creatinine ratio ≤ 0.5), reflecting the higher presence of monocytes/lymphocytes in the urine of subjects with active lupus nephritis (Figure 6G).…”

Section: Immune Signatures In Lupus Nephritismentioning

confidence: 99%

Urine Single-Cell RNA Sequencing in Focal Segmental Glomerulosclerosis Reveals Inflammatory Signatures

Latt

Heymann

Jessee

et al. 2022

Kidney International Reports

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…77 Recent initiatives of industry-academia collaborations, such as the Innovative Medicines Initiative in Europe ($5B), the Accelerating Medicines Partnership in the U.S. ($215M), and the Precision Medicine Initiative in China ($9.2B), are parts of larger strategies with expected long-term benefits. [78][79][80] These initiatives invest in basic science and biomedical research capabilities in universities. India could leverage its strength in pharmaceuticals and information technology by undertaking a similar initiative.…”

Section: Pillar 2: Precision Medicinementioning

confidence: 99%

A Strategic Research Framework for Defeating Diabetes in India: A 21st-Century Agenda

et al. 2023

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Indian people are at high risk for type 2 diabetes (T2DM) even at younger ages and lower body weights. Already 74 million people in India have the disease, and the proportion of those with T2DM is increasing across all strata of society. Unique aspects, related to lower insulin secretion or function, and higher hepatic fat deposition, accompanied by the rise in overweight (related to lifestyle changes) may all be responsible for this unrelenting epidemic of T2DM. Yet, research to understand the causes, pathophysiology, phenotypes, prevention, treatment, and healthcare delivery of T2DM in India seriously lags behind. There are major opportunities for scientific discovery and technological innovation, which if tapped can generate solutions for T2DM relevant to the country’s context and make leading contributions to global science. We analyze the situation of T2DM in India, and present a four-pillar (etiology, precision medicine, implementation research, and health policy) strategic research framework to tackle the challenge. We offer key research questions for each pillar, and identify infrastructure needs. India offers a fertile environment for shifting the paradigm from imprecise late-stage diabetes treatment toward early-stage precision prevention and care. Investing in and leveraging academic and technological infrastructures, across the disciplines of science, engineering, and medicine, can accelerate progress toward a diabetes-free nation.

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Accelerating Medicines Partnership: Organizational Structure and Preliminary Data From the Phase 1 Studies of Lupus Nephritis

Cited by 21 publications

References 42 publications

Lupus Susceptibility Loci Predispose Mice to Clonal Lymphocytic Responses and Myeloid Expansion

Lupus Susceptibility Loci Predispose Mice to Clonal Lymphocytic Responses and Myeloid Expansion

Urine Single-Cell RNA Sequencing in Focal Segmental Glomerulosclerosis Reveals Inflammatory Signatures

A Strategic Research Framework for Defeating Diabetes in India: A 21st-Century Agenda

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