AT-300 / Akashi Therap - LARVOL DELTA

A phase 1 study of alpha-1,3-galactosyltransferase-expressing allogeneic renal cell carcinoma immunotherapy in patients with metastatic renal cell cancer. (ASCO-GU 2017) - P1; "...Background: HyperAcute Renal (HAR) immunotherapy consists of two allogeneic renal cancer cell lines that have been genetically modified to express the carbohydrate α(1,3)Gal, to which humans have an inherent pre-existing immunity... RCC is considered an immunogenic tumor based on its response rate to immune checkpoint blockade and IL-2, occasional spontaneous regression, and the high level of tumor T cell infiltration. HAR was well tolerated in this patient population. Therefore, RCC is an appropriate tumor type to target with combination immunotherapy including HAR."

Checkpoint inhibition • P1 data • Renal Cell Carcinoma

Clinical activity and safety of ASN001, a selective CYP17 lyase inhibitor, administered without prednisone in men with metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2017) - P1/2; "While the Phase 1 also allowed enrollment of pretreated patients, no prior enzalutamide (ENZA) or abiraterone (ABI) is permitted in Phase 2. Overall, ASN001 was safe and well tolerated without need for prednisone co-administration. Encouraging preliminary evidence of efficacy is based on the PSA decline observed in evaluable mCRPC pts not pretreated with ABI or ENZA and based on durable disease stabilization after progression on ABI and ENZA. Enrollment is ongoing at doses below 400mg QD in ABI/ENZA naïve mCRPC pts."

Clinical • Biosimilar • Oncology • Prostate Cancer • Urothelial Cancer

A phase II study of the anti-programmed death ligand-1 antibody durvalumab (D; MEDI4736) in combination with PARP inhibitor, olaparib (O), in metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2017) - P1/2; "...Prior treatment with enzalutamide and/or abiraterone is required... Exploiting synergy of D+O is a treatment option for heavily pre-treated pts. Preliminary data shows D+O is tolerable and active in mCRPC pts without germline BRCA mutation. Paired tumor biopsies and blood samples including ctDNA are being collected."

Biomarker • Checkpoint inhibition • Clinical • P2 data • Prostate Cancer

Piezo1 acts upstream of TRPV4 to induce pathological changes in endothelial cells due to shear stress. (PubMed, J Biol Chem) - "The ion channels Piezo1 and TRPV4 have both, independently, been implicated in high venous pressure- and fluid shear stress-induced vascular hyperpermeability in endothelial cells.  However, the mechanism by which Piezo1 and TRPV4 channels execute the same function is poorly understood.  Here we demonstrate that Piezo1 regulates TRPV4 channel activation in endothelial cells and that Piezo1-mediated TRPV4 channel opening is a function of the strength and duration of fluid shear stress.  We first confirmed that either fluid shear stress or the Piezo1 agonist, Yoda1, led to an elevation in intracellular calcium ([Ca2+]i), and that application of the Piezo1 antagonist, GsMTx4, completely blocked this change. We discovered that high and prolonged shear stress caused sustained [Ca] elevation which was blocked by inhibition of TRPV4 channel opening.  Moreover, Piezo1 stimulated TRPV4 opening through activation of phospholipase A2.  TRPV4-dependent..."

Journal

Piezo1 channels mediate trabecular meshwork mechanotransduction and promote aqueous fluid outflow. (PubMed, J Physiol) - "Trabecular meshwork (TM) is a highly mechanosensitive tissue in the eye that regulates intraocular pressure through the control of aqueous humor drainage. Its dysfunction underlies the progression of glaucoma but neither the mechanisms through which TM cells sense pressure nor their role in aqueous humor outflow are understood at the molecular level. We identified the Piezo1 channel as a key TM transducer of tensile stretch, shear flow and pressure. Its activation resulted in intracellular signals that altered organization of the cytoskeleton and cell-extracellular matrix contacts and modulated the trabecular component of aqueous outflow whereas another channel, TRPV4, mediated a delayed mechanoresponse. This study helps elucidate basic mechanotransduction properties that may contribute to intraocular pressure regulation in the vertebrate eye."

Journal • Glaucoma • Ophthalmology

Yoda1 and phosphatidylserine exposure in red cells from patients with sickle cell anaemia. (PubMed, Sci Rep) - "Yoda1 caused an increase in [Ca] and PS exposure, which was inhibited by its antagonist Dooku1 and the PIEZO1 inhibitor GsMTx4, consistent with functional PIEZO1...Two PKC inhibitors were also tested, chelerytherine chloride and calphostin C. Both reduced PS exposure whilst chelerytherine chloride also reduced Yoda1-induced increases in [Ca]. Findings are therefore consistent with the presence of PIEZO1 in sickle cells, able to mediate Ca entry but that PKC was also involved in both Ca entry and PS exposure."

Clinical • Journal • Anemia • Hematological Disorders • Sickle Cell Disease

Suppression of hypersynchronous network activity in cultured cortical neurons using an ultrasoft silicone scaffold. (PubMed, Soft Matter) - "The dose of GsMTx-4, an antagonist of stretch-activated cation channels (SACs), required to reduce the generation of the events below 1.0 event per min on PDMS substrates was lower than that for neurons on a glass substrate. This suggests that the difference in the baseline level of SAC activation is a molecular mechanism underlying the alteration in neuronal network activity depending on scaffold stiffness. Our results demonstrate the potential application of PDMS with biomimetic elasticity as cell-culture scaffold for bridging the in vivo-in vitro gap in neuronal systems."

Journal • Preclinical

Inhibiting the Piezo1 channel protects microglia from acute hyperglycaemia damage through the JNK1 and mTOR signalling pathways. (PubMed, Life Sci) - "Piezo1 is necessary for microglial damage in acute hyperglycaemia and may become a promising target to treat hyperglycaemic brain injury."

Journal • CNS Disorders • Cognitive Disorders • Diabetes • Immunology • Inflammation • Metabolic Disorders • Vascular Neurology • MAPK8

Transgenic Tarantula Toxin: a novel tool to study mechanosensitive ion channels in Drosophila. (PubMed, J Insect Physiol) - "Expression of GsMTx4 in these neurons results in robust inhibition of mechanical nociception, demonstrating the toxin is active when expressed in vivo. The tool will be particularly useful to manipulate MSC activity in a spatially and temporally-controlled manner to study their role in development, physiology and behaviour in intact, free moving animals."

Journal

Association of Genetic Variants at TRPC6 With Chemotherapy-Related Heart Failure. (PubMed, Front Cardiovasc Med) - "Background: Our previous GWAS identified genetic variants at six novel loci that were associated with a decline in left ventricular ejection fraction (LVEF), p < 1 × 10 in 1,191 early breast cancer patients from the N9831 clinical trial of chemotherapy plus trastuzumab...Doxorubicin-induced apoptosis and cardiomyopathy was modeled in human iPSC-derived cardiomyocytes and endothelial cells and a mouse model, respectively, that were pre-treated with GsMTx-4, an inhibitor of TRPC6...GsMTx-4 may be a cardioprotective agent in patients with TRPC6 risk variants. Replication of the genetic associations in larger well-characterized samples and functional studies are required."

Journal • Breast Cancer • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Oncology • Solid Tumor

Activation of Piezo1 sensitizes cells to TRAIL-mediated apoptosis through mitochondrial outer membrane permeability. (PubMed, Cell Death Dis) - "GsMTx-4, a Piezo1 inhibitor, was found to reduce shear stress-related TRAIL sensitization, implicating Piezo1 activation as a potential TRAIL-sensitizer...From these experiments a computational model was developed to simulate apoptosis for cells treated with TRAIL and increased calcium. The computational model elucidated the proapoptotic or antiapoptotic roles of Bax, Bcl-2, XIAP, and other proteins important in the mitochondrial-apoptotic signaling pathway."

Journal • Oncology

Bile canaliculi contract autonomously by releasing calcium into hepatocytes via mechanosensitive calcium channel. (PubMed, Biomaterials) - "The Piezo-1 inhibitor GsMTx-4 blocks the Ca transfer, resulting in cholestatic generation of BC-derived vesicles whereas Piezo-1 hyper-activation by Yoda1 increases the frequency of Ca transfer and BC contraction cycles. Yoda1 can recover normal BC contractility in drug-induced hepatocellular cholestasis, supporting that Piezo-1 regulates BC contraction cycles. Finally, we show that hyper-activating Piezo-1 can be exploited to normalize bile flow in drug-induced hepatocellular cholestasis."

Journal • Cholestasis • Hepatology

Piezo channel plays a part in retinal ganglion cell damage. (PubMed, Exp Eye Res) - "On the other hand, Piezo antagonist GsMTx4 promoted neurite outgrowth in retinal ganglion cells. These findings indicate that Piezo channel may contribute to diseases relating the IOP such as glaucoma."

Journal • Glaucoma • Ophthalmology • Retinal Disorders

Mechanotransduction via the Piezo1-Akt pathway underlies Sost suppression in osteocytes. (PubMed, Biochem Biophys Res Commun) - "We also demonstrated that mechanical stretch of IDG-SW3 suppressed Sost expression, a result which was abrogated by treatment with the Piezo1 inhibitor GsMTx4, and the deficiency of Piezo1. Furthermore, the suppression of Sost expression was abolished by treatment with an Akt inhibitor. Taken together, these results indicate that the activation of the Piezo1-Akt pathway in osteocytes is required for mechanical stretch-induced downregulation of Sost expression."

Journal

Shear stress induced nuclear shrinkage through activation of Piezo1 channels in epithelial cells. (PubMed, J Cell Sci) - "Inhibiting mechanosensitive Piezo1 channels through treatment with GsMTx4 prevented nuclear shrinkage...To ascertain the relative contributions of Ca to cytoskeleton perturbation, we examined the F-actin reorganization under shear stress and static conditions, and showed that reorganization of the cytoskeleton is not necessary for nuclear shrinkage. These results emphasize the role of the mechanosensitive channels as primary transducers in force transmission to the nucleus."

Journal

Inhibition of Piezo1 attenuates demyelination in the central nervous system. (PubMed, Glia) - "GsMTx4 also attenuated both LPC-induced astrocyte toxicity and microglial reactivity within the lesion core. Overall, our data suggest that pharmacological activation of Piezo1 channels induces demyelination and that inhibition of mechanosensitive channels, using GsMTx4, may alleviate the secondary progressive neurodegeneration often present in the latter stages of demyelinating diseases."

Journal • CNS Disorders • Solid Tumor

Piezo1 regulates calcium oscillations and cytokine release from astrocytes. (PubMed, Glia) - "However, LPS-stimulated astrocyte cultures exposed to the Piezo1 activator, Yoda1, migrated significantly slower than reactive astrocytes treated with the mechanosensitive channel-blocking peptide, GsMTx4. Furthermore, our data show that activating Piezo1 channels inhibits the release of cytokines and chemokines, such as IL-1β, TNFα, and fractalkine (CX CL1), from LPS-stimulated astrocyte cultures. Taken together, our results suggest that astrocytic Piezo1 upregulation may act to dampen neuroinflammation and could be a useful drug target for neuroinflammatory disorders of the brain."

Journal • Alzheimer's Disease • CNS Disorders • Immunology • Solid Tumor

Functional Expression of Piezo1 in Dorsal Root Ganglion (DRG) Neurons. (PubMed, Int J Mol Sci) - "The Yoda1-induced Ca response is inhibited by cationic channel blocker, ruthenium red and cationic mechanosensitive channel blocker, GsMTx4...Piezo1 also shows physiological functions with transient receptor potential vanilloid 1 (TRPV1) in the same DRG neurons and is regulated by the activation of TRPV1 in mouse DRG sensory neurons. Overall, we found that Piezo1 has physiological functions in DRG neurons and that TRPV1 activation inhibits an inward current induced by Yoda1."

Journal • Pain

Regional Heterogeneity in the Mechanisms of Myogenic Tone in Hamster Arterioles. (PubMed, Am J Physiol Heart Circ Physiol) - "Thus, there are substantial differences in the mechanisms underlying myogenic tone in hamster cremaster and cheek pouch arterioles. Regional heterogeneity in myogenic mechanisms could provide new targets for drug development to improve regional blood flow in a tissue-specific manner."

Journal • Biosimilar

Effects of thermal-stress and glycan-removal on structural integrity of a human IgG1 antibody: Insights from extended molecular dynamics simulations (ACS-Sp 2017) - "The glycan-removal, on the other hand, leads to perturbation of the CH2 domain quaternary structure. These simulations have led to an improved understanding of the effect of inherent conformational dynamics on physicochemical degradation (for example, aggregation, oxidation, deamidation) of an antibody molecule."

Clinical • Biosimilar

Mechanical Alterations during 800-m Self-Paced Track Running. (PubMed) - Int J Sports Med - "While vertical ground force characteristics remained unchanged, non-specialist runners produced lower peak braking and push-off forces, in turn leading to shorter stride length. Spring-mass model characteristics changed toward lower vertical stiffness values, whereas leg stiffness did not change."

Journal • Biosimilar

Cathelicidin antimicrobial peptide from Alligator mississippiensis has antibacterial activity against multi-drug resistant Acinetobacter baumanii and Klebsiella pneumoniae. (PubMed) - Dev Comp Immunol - "It is possible that the alligator cathelicidins play an important role in the innate immune response of A. mississippiensis, similar to LL-37 in humans. In addition, due to their activities against MDR bacteria and lack of cytotoxicity, the AM-CATH peptides could be an attractive platform for further development as a potential therapeutic."

Journal • Biosimilar • Immunology

GsMTx4: Mechanism of Inhibiting Mechanosensitive Ion Channels. (PubMed) - "These data suggest a model placing GsMTx4 at the membrane surface, where it is stabilized by the lysines, and occupying a small fraction of the surface area in unstressed membranes. When applied tension reduces lateral pressure in the lipids, the peptides penetrate deeper acting as "area reservoirs" leading to partial relaxation of the outer monolayer, thereby reducing the effective magnitude of stimulus acting on the MSC gate."

Journal • Biosimilar

Biochar decreases nitrogen oxide and enhances methane emissions via altering microbial community composition of anaerobic paddy soil. (PubMed) - Sci Total Environ - "However, larger pore size of B500 and B700 (surface area of 68.1 and 161m(2)g(-1)) than B300 (4.40m(2)g(-1)) favored electron transfer between bacteria and iron minerals, leading to increased abundance of iron-reducing bacteria, (e.g., Clostridia, 48.2-50.6 vs. 33.3%), which competed with methanogens to produce CH4, thereby leading to lower increase in CH4 emission. Biochar amendments with high pH and surface area might be effective to mitigate emission of both N2O and CH4 from paddy soil."

Journal • Biosimilar

A Phase I Dose Finding Trial of Eltrombopag during Consolidation Therapy in Adults with Acute Myeloid Leukemia Employing a Unique Dosing Design: PrE0901, a Precog Study (ASH 2016) - "Endogenous cytokine (TPO and EPO) levels varied inversely with plt and hematocrit values and did not appear to be affected by eltrombopag dose / schedule (details to be provided at ASH Annual Mtg). Unusually high screen fail numbers warrant examination to guide future trial design in the post-remission setting. The addition of eltrombopag to high-dose cytarabine consolidation therapy was well-tolerated and no DLTs were observed."

Clinical • P1 data • Acute Myelogenous Leukemia • Biosimilar • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Oncology • Venous Thromboembolism