small interfering RNA anti-fibrotic / Nitto Denko, SBI Biotech - LARVOL DELTA

A novel bispecific siRNA concept: Efficient dual knockdown of YAP1 and WWTR1 with a single guide strand. (PubMed, Mol Ther Nucleic Acids) - "Additionally, a chemically modified bispecific siRNA showed effective knockdown in vivo. Our data demonstrate the potential for using a bispecific siRNA targeting YAP1/WWTR1 as a therapeutic agent for liver diseases, presenting a novel approach for dual targeting with a simple conventional siRNA structure."

Journal • Fibrosis • Hepatology • Immunology • Oncology • WWTR1 • YAP1

A Randomized Sham-Controlled Phase 2/3 Trial of QPI-1007 for Acute Nonarteritic Anterior Ischemic Optic Neuropathy. (PubMed, Ophthalmology) - "IVT injection of QPI-1007 in eyes with acute NAION was well-tolerated. Although the primary outcome measure was not met, there were significant effects on preserving vision in the subgroup of participants with baseline BCVA of ≤ 20/63."

Journal • P2/3 data • Ocular Inflammation • Ophthalmology • Optic Neuritis • Pain

Bispecific small interfering RNA targeting YAP1/WWTR1 reduces low-density lipoprotein-cholesterol via proprotein convertase subtilisin/kexin type 9 transcriptional regulation in metabolic dysfunction-associated steatotic liver diseases (EASL 2025) - "Dual silencing of Yap1/Wwtr1 lowers plasma LDL-C levels by decreasing Pcsk9 transcription in mice. bsiYW is a potential therapeutic agent for preventing and treating MASLD-related CVD. Blood PCSK9 levels could serve as proof of mechanism for YAP/TAZ inhibition in the liver and as a biomarker to identify responsive patients."

Dyslipidemia • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • CCN1 • CTGF • WWTR1 • YAP1

Bispecific small interfering RNA targeting YAP1/WWTR1 as a novel therapeutic agent for metabolic dysfunction-associated steatohepatitis (EASL 2025) - "Dual silencing of YAP1 and WWTR1 synergistically suppressed the YAP/TAZ pathway in vitro and in vivo. bsiYW ameliorated hepatic steatosis and fibrosis in CDAHFD-fed mice depending on the hepatocytes-derived mechanisms, such as remodeling of lipid composition, at least in part. These findings suggest that bsiYW could be a novel therapeutic approach for MASH."

Fibrosis • Hepatology • Immunology • Liver Cancer • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Oncology • Solid Tumor • TAFAZZIN • WWTR1 • YAP1

DUAL SILENCING OF YAP1/WWTR1 AS A NOVEL THERAPEUTICAL APPROACH FOR LIVER FIBROSIS (AASLD 2024) - "In vitro study, negative control siRNA (siNC), siRNA targeting YAP1 and/or WWTR1 were transfected in HepG2 (human hepatoma cell line) and LX-2 (human hepatic stellate cell line) cells, and then gene expression levels were determined... Dual silencing of YAP1/WWTR1 suppressed YAP/TAZ pathway synergistically in vitro, and ameliorated steatosis and fibrosis in the liver of CDAHFD fed mice with advanced fibrosis. These findings suggest that dual silencing of YAP/TAZ would be a novel therapeutical approach for advanced fibrosis in MASH."

Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Inflammation • Liver Cancer • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Solid Tumor • ANKRD1 • CCL2 • CCN1 • COL1A1 • CTGF • IL1B • TGFB1 • TIMP1 • TNFA • WWTR1 • YAP1

First-in-human dose-escalation study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with non-small cell lung, pancreatic, or colorectal cancer. (ASCO 2023) - P1 | "This FIM study with NBF-006 demonstrated a favorable safety profile with early signs of antitumor activity in NSCLC. No DLTs or treatment-related SAEs were observed. Dose expansion in NSCLC is ongoing and will not be presented."

Clinical • P1 data • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Lung Cancer • Musculoskeletal Pain • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • GSTP1 • KRAS

Teprasiran, A Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study. (PubMed, Circulation) - P2, P3 | "A Phase 3 study with a MAKE90 primary outcome which has recently completed enrollment was designed based on these findings (NCT03510897). Clinical Trial Registration: URL: https://clinicaltrials.gov/ Unique Identifier: NCT02610283."

Clinical • Journal • Acute Kidney Injury • Cardiovascular • Nephrology • Renal Disease • CST3

Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression. (PubMed) - J Am Soc Nephrol - "These results uncovered the important role of EZH2 in mediating the development of renal fibrosis by downregulating expression of Smad7 and PTEN, thus activating profibrotic signaling pathways. Targeted inhibition of EZH2, therefore, could be a novel therapy for treating CKD."

Journal • Biosimilar • Fibrosis • Immunology • Inflammation • Oncology • Systemic Sclerosis

Src inhibition blocks renal interstitial fibroblast activation and ameliorates renal fibrosis. (PubMed) - "Src inhibition also suppressed activation of TGF-β1 signaling, activation of the epidermal growth factor receptor and STAT3, and reduced the number of renal epithelial cells arrested at the G2/M phase of the cell cycle after ureteral obstruction. Thus, Src is an important mediator of renal interstitial fibroblast activation and renal fibrosis, and we suggest that Src is a potential therapeutic target for treatment of chronic renal fibrosis.Kidney International advance online publication, 7 October 2015; doi:10.1038/ki.2015.293."

Journal • Biosimilar • Fibrosis • Immunology • Inflammation • Oncology • Renal Cell Carcinoma • Renal Disease • Systemic Sclerosis

Notch3 Ameliorates Cardiac Fibrosis After Myocardial Infarction by Inhibiting the TGF-β1/Smad3 Pathway. (PubMed) - "Notch3 cDNA treatment also increased MMP-9 expression and decreased TIMP-2 expression in the TGF-β1-stimulated cells. This study indicates that Notch3 is an important protective factor for cardiac fibrosis in a MI model, and the protective effect of Notch3 is attributable to its action on TGF-β1/Smad3 signaling."

Journal • Acute Coronary Syndrome • Biosimilar • Fibrosis • Immunology • Inflammation • Systemic Sclerosis

In Vivo Gene-Silencing in Fibrotic Liver by siRNA-Loaded Cationic Nanohydrogel Particles. (PubMed) - Adv Healthc Mater - "Cationic nanohydrogel particles loaded with anti-Col1α1 siRNA suppress collagen synthesis and deposition in fibrotic mice: Systemically administered 40 nm sized nanogel particles accumulate in collagen-expressing cells in the liver. Their siRNA payload induces a sequence specific in vivo gene knockdown affording an efficient antifibrotic effect in mice with liver fibrosis."

Journal • Biosimilar • Fibrosis • Immunology • Inflammation • Systemic Sclerosis

Essential Roles of RNA-binding Protein HuR in Activation of Hepatic Stellate Cells Induced by Transforming Growth Factor-β1. (PubMed) - Sci Rep - "Pharmacological or siRNA-induced SphK1 inhibition abrogated HuR-mediated HSC activation. In conclusion, our data suggested that HuR bound to SphK1 mRNA and played a crucial role in TGF-β1-induced HSC activation."

Journal • Biosimilar • Fibrosis • Systemic Sclerosis

Regulation of transforming growth factor-beta1 (TGF-β1)-induced pro-fibrotic activities by circadian clock gene BMAL1. (PubMed) - Respir Res - "Our results indicate that activation of TGF-β1 promotes the transcriptional induction of BMAL1. Furthermore, BMAL1 is required for the TGF-β1-induced signaling transduction and pro-fibrotic activities in the lung."

Journal • Biosimilar • Fibrosis • Immunology • Inflammation • Oncology • Systemic Sclerosis