Benaroya Research Institute (BRI) is a Seattle, Washington non-profit organization that conducts medical research on many diseases and immune disorders, including autoimmune disease. It is affiliated with Virginia Mason Health System, and is located on the campus of Virginia Mason Medical Center.Much of BRI's research aims to understand how immune cells function and why they malfunction to cause disease. BRI researchers study how immune cells contribute to rheumatoid arthritis, type 1 diabetes, multiple sclerosis and other diseases.BRI uses translational research and clinical trials to carry its findings from the lab to the clinic, to inform how physicians diagnose and treat disease.
The dual-specificity, tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is intensively studied because of its implication in numerous human diseases (Down syndrome, Alzheimer’s disease, type 2 diabetes, myocardial infarction, various cancers and leukaemia, etc.). Several GWAS studies have identified DYRK1A as a risk factor for Parkinson’s disease (PD). DYRK1A indeed phosphorylates at least 20 proteins clearly involved in PD: AMPH, CASP9, DYN1, FOXO, GSK3B, MAP1B, MAPT, MEF2D, NFAT, TP53, PRKN, PLK2, RABs, RCAN1, SEPT4, SNCA, STAT3, SYNJ1, TOM70, WASL. Several other proteins involved in PD interact with DYRK1A: calpains, DSCAM, REST/NRSF, 14-3-3. DYRK1A is involved in axonal transport, neural stem cells proliferation and differentiation, and neuroinflammation. A few DYRK1A inhibitors have been tested on PD models, generally showing protective effects.The overall picture provided by this comprehensive review on the links between DYRK1A and PD advocates for more fundamental studies to understand how DYRK1A participates to the onset and development of PD and dementia with Lewy bodies (DLB), two closely related disorders. It also encourages the evaluation of well-characterized pharmacological modulators of DYRK1A as therapeutic approaches to various aspects of PD and DLB.
The primary objective of this study was to investigate whether ligand-receptor interactions (LRIs) between IGHG and FCGR gene products are associated with progression to type 1 diabetes (T1D). Using two completed clinical trials (DPT-1 and TN07), we applied next-generation targeted sequencing to genotype IGHG and FCGR genes in a cohort of 1,214 individuals and assessed LRI associations with disease progression. A Cox regression model was used to quantify LRI associations. IGHG or FCGR alone was found to have weak and sporadic associations with progression. Multiple LRIs between IGHG and FCGR gene products were found to be associated with progression, especially LRIs of IGHG2 with multiple FCGR receptors that accelerate progression and those of IGHG4 with multiple FCGR receptors (some overlapping) that delay progression. Furthermore, as several crystal structures of FcγRs complexed with distinct IgG molecules are known, application of this knowledge here was hampered by the absence of any information on the subclass distribution of each of the several T1D-related autoantibodies. It cannot be excluded that their respective state of glycosylation may influence binding affinity to various FcγRs and the function of thus-formed complexes. Our findings suggest that LRIs of the IGHG and FCGR gene products probably influence progression, shedding new insights into some of the immunological mechanisms involved in progression to T1D. Our findings potentially facilitate the search for new immunotherapeutic treatment through intervening at key steps in the progression. ARTICLE HIGHLIGHTS:This study investigated ligand-receptor interactions (LRIs) between IGHG and FCGR gene products in type 1 diabetes progression. Genes of 1,214 participants from the DPT-1 and TN07 trials were sequenced using next-generation targeted sequencing technology, and LRI associations with the progression time to type 1 diabetes were analyzed using Cox regression modeling. Weak associations were found for IGHG or FCGR variants individually, but multiple LRIs significantly impacted progression. Several IGHG2-FCGR interactions accelerated progression, while a few other IGHG4-FCGR interactions delayed it. The results may provide insights into certain immunogenetic mechanisms of T1D and suggest therapeutic potential of targeting specific LRIs.
Objective: Long-term side effect surveillance after immunotherapy clinical trial participation in individuals with, or at risk for, type 1 diabetes is needed. Research Design and Methods: Participants from 14 randomized controlled trials (47%) joined Long-term Investigative Follow-Up in Type 1 Diabetes TrialNet or Immune Tolerance Network Type 1 Diabetes Extension Study and 98% answered at least one health-related outcomes question. Results: Participants were followed for a median of 1.78 years (IQR 0.89-4.04) after original trial completion and, in some, up to 18 years. There were no differences in the frequency of self-reported health outcomes including moderate-to-severe hypoglycemia events, hospitalizations, serious infections (including COVID-19 infection), new allergic reactions, autoimmune disease, and cancer incidence between active and placebo therapy (p>0.05 for all, n=209-473 responses per question). Conclusions: We observed no difference in self-reported health outcomes between those who received active immunotherapy versus placebo. Continued long-term follow-up of immunotherapy trial participants is essential.
Abstract Introduction Engineered regulatory T cell (EngTreg) therapy offers a novel approach to restore immune tolerance in type 1 diabetes (T1D). To support POLARIS, GentiBio’s first-in-human trial of GNTI-122, we developed a biomarker program to monitor drug kinetics, pharmacodynamics, and immunogenicity. Methods Kinetics of GNTI-122 will be quantified by droplet digital PCR (ddPCR) detecting engineered transgenes. An 18-color flow cytometry panel is designed to detect GNTI-122, its Treg profile, and impact on immune subsets. Mechanism of action of GNTI-122 will be assessed by reduction in β cell-specific effector T cell (Teffs) responses using two complementary assays: an Activation-Induced Marker (AIM) assay and a FluoroSpot assay. Immunogenicity will be evaluated by a cell-based anti-drug antibody (ADA) assay targeting the TCR of GNTI-122. Results Biomarker assays demonstrated robust sensitivity, specificity and precision. Validated assays show the ability to detect GNTI-122 at a level of sensitivity < 0.1% of total WBCs. AIM and FluoroSpot assays reproducibly detected β cell-specific Teffs. Our cell-based anti-TCR ADA assay detected anti-TCR antibodies at a sensitivity < 850 ng/ml. Conclusion This comprehensive biomarker strategy provides a rigorous translational framework to monitor cellular kinetics, pharmacodynamics, and immunogenicity, to elucidate biological mechanisms of GNTI-122 for GentiBio’s POLARIS Phase 1 safety trial of GNTI-122 in recently diagnosed T1D. Funding Source T1D Fund Topic Categories Immune Mechanisms of Human Disease (HUM)
