Topas Therapeutics GmbH’s Post

Fibrosis is commonly associated with chronic rheumatic diseases, and causes substantial morbidity and mortality. Treatment of fibrosis is extremely challenging but is badly needed, as approved antifibrotic therapies fibrosis do not halt its progression, which will be discussed with a focus on pulmonary fibrosis. Findings from recent studies indicate several therapeutic targets for treating fibrosis. Interleukin-11 is emerging as a fibrogenic cytokine whose activity can be blocked with neutralizing monoclonal antibodies. Fibroblast activation protein (FAP) is highly expressed by activated fibroblasts in inflammatory and fibrotic tissues. Targeting FAP with different modalities has been extensively explored as adjunct treatment for cancer, which can also apply to treating fibrosis in rheumatic diseases.

The authors of this recently published article highlight the critical role of Gprasp1 and Gprasp2 proteins in regulating the stability and cellular trafficking of CXCR4, essential for B-cell trafficking in the germinal center. Deficiency in these proteins leads to transcriptional abnormalities and a significant risk of aggressive B-cell hyperproliferative diseases, closely resembling human high-grade B-cell lymphomas. Read more in our November issue 👉

A recent study explored the effects of 𝐉𝐀𝐊 𝐢𝐧𝐡𝐢𝐛𝐢𝐭𝐨𝐫𝐬 (JAKi) and biological DMARDs (bDMARDs) on rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Here are the key findings: 1️⃣ 93 RA patients with ILD were analyzed, with JAKi and abatacept showing comparable efficacy in managing RA-ILD. 2️⃣ About 19.4% of patients experienced worsening ILD, with the extent of fibrotic lesions and female gender identified as significant risk factors. 3️⃣ Patients receiving methotrexate (MTX) demonstrated a lower rate of worsening ILD, suggesting MTX may help modify the disease course. 4️⃣ In cell studies, both MTX and baricitinib inhibited the epithelial-mesenchymal transition (EMT) induced by IL-6, highlighting their potential combined therapeutic effect against fibrosis. These findings underscore the importance of tailored treatment strategies for RA-ILD patients. Further research is necessary to refine our understanding and improve outcomes. Read the full article here: https://lnkd.in/ejeSxCt6 #RheumatoidArthritis #JAKinhibitors

Druggability, molecular targets, and nanocarrier delivery of natural triterpenoid celastrol against chronic diseases https://lnkd.in/empjwCmJ #cancer #Celastrol #diabetes #inflammation #neurodegeneration #obesity

Metabolic dysfunction may increase the risk of liver-related events and hepatocellular carcinoma (HCC) in patients with chronic hep C virus (HCV) who achieved sustained virologic response (SVR) with direct-acting antiviral (DAA) therapy. https://lnkd.in/eS4xQNbq

Interesting in Cell: Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis https://lnkd.in/dDq-Txyx Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov(NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.

Three people with autoimmune diseases (one patient with immune-mediated necrotizing myopathy (IMNM) and two patients with diffuse cutaneous systemic sclerosis (dcSSc), have responded positively to allogeneic CAR-T therapy, marking a first for the "off-the-shelf" cell therapy tech which is engineered CAR-T cells from donors to target CD19, a protein found on the surface of B cells. They also knocked out human leukocyte antigen in the cells and then amplified the cells negative for CD3, in order to prevent conflicts between donor cells and host cells. CD19 targeting is an emerging therapy for treating B cell malignancies, but it hasn’t successfully been used to treat B cells that have gone rogue, as is the case in autoimmune diseases. The study, conducted in China and published in Cell on July 15, is the first sign of the potential of allogeneic CAR-T therapies in treating autoimmune diseases

Chitinase 3-Like 1 Protein: A Promising Biomarker for Fibrosis and Inflammatory Diseases Chitinase 3-like 1 protein (CHI3L1), also known as YKL-40, is emerging as a pivotal biomarker in the assessment of fibrosis and chronic inflammatory conditions. 🧬 Biological Role of CHI3L1 CHI3L1 is a glycoprotein secreted by activated macrophages, neutrophils, and chondrocytes. It plays a key role in: Tissue remodeling Fibrotic processes Inflammatory signaling pathways Elevated CHI3L1 levels are indicative of tissue damage, chronic inflammation, and fibrosis, particularly in hepatic pathologies. 🔬 CHI3L1 in Fibrosis Research 1️⃣ Hepatic Fibrosis: CHI3L1 is significantly elevated in patients with chronic liver diseases (CLD), such as hepatitis B, hepatitis C, and non-alcoholic fatty liver disease (NAFLD). It correlates with the degree of fibrosis, offering potential as a non-invasive biomarker for staging hepatic fibrosis and predicting disease progression. 2️⃣ Hepatocellular Carcinoma (HCC): In patients with CLD, increased CHI3L1 levels may signal a transition from fibrosis to malignancy, serving as a prognostic marker for HCC. 3️⃣ Systemic Fibrosis: Beyond the liver, CHI3L1 is implicated in fibrotic processes affecting other organs, such as in pulmonary fibrosis and cardiovascular diseases. 🔍 Why CHI3L1 is Crucial for Clinical Practice Non-Invasive Diagnostics: CHI3L1 could reduce the reliance on invasive biopsies for assessing fibrosis severity. Early Detection: Its correlation with fibrotic progression provides clinicians with an opportunity for earlier intervention. Therapeutic Monitoring: CHI3L1 may also serve as a marker for evaluating the efficacy of antifibrotic therapies. As a researcher specializing in tumor markers and fibrosis diagnostics, my work focuses on expanding the clinical applications of CHI3L1 to enhance patient care in chronic liver disease and beyond. Stay connected for more insights into the rapidly evolving field of fibrosis biomarkers. https://lnkd.in/eTmrf_9v #Chitinase3Like1 #FibrosisResearch #HepaticFibrosis #TumorMarkers #ChronicLiverDisease #NonInvasiveDiagnostics #LiverHealth #ClinicalResearch #BiomarkersInMedicine

Memory T cells are conventionally subdivided into T central memory (TCM) and T effector memory (TEM) cells. However, a newly recognized subset of memory T cells, termed T memory stem cells (TSCM), exhibits characteristics of both TCM and TEM cells, including lymphoid homing and effector roles such as cytokine secretion, including interleukin-2 (IL-2) and interferon-gamma (IFN-γ). TSCM cells possess unique biological properties, including stemness, antigen independence, high proliferative capacity, signaling pathway regulation, and lipid metabolism. Memory T cells play a pivotal role in the pathogenesis of autoimmune diseases. TSCM cells contribute to long-term defensive immunity against foreign antigens and tumor-associated antigens, often derived from self-antigens. Antigen-specific TSCM cells have demonstrated the ability to mount antitumor responses that may also induce autoimmune activities. Recent evidence highlights the functions of TSCM cells in autoimmune disorders such as type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, acquired aplastic anemia, immune thrombocytopenia, and autoimmune uveitis. Furthermore, TSCM cells are introduced as innovative prognostic biomarkers and promising therapeutic targets in autoimmune disease management.