SJP-0008 / Senju Pharmaceutical - LARVOL DELTA

Using fibre photometry with a fluorescence resonance energy transfer-based biosensor to test efficacy of calpain inhibitors in vivo. (PubMed, Brain Commun) - "This methodology was used to compare within-animal responses to different doses and administration routes of several calpain inhibitor compounds, including calpeptin, BLD-2736 and SNJ-1945...To our knowledge, this is the first report of real-time measurement of neuronal calpain activity in vivo. Future experiments could exploit this novel methodology to obtain calpain activity measurements alongside other pharmacological and behavioural/physiological measurements to increase the translational validity of preclinical models for drug development in diseases characterized by calpain overactivity."

Journal • Preclinical • CNS Disorders • Developmental Disorders

Safety and Efficacy of Orally Administered SJP-0008 in Central Retinal Artery Occlusion: A Phase IIa Randomized Clinical Trial. (PubMed, Ophthalmol Sci) - "However, large-scale, multicenter randomized controlled trials are warranted to validate the findings of this study. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article."

Clinical • Journal • P2a data • Retinal Disorders

Calcium-dependent pathway as a primary cause of hypoxic RGC damage in monkey retinal explants. (PubMed, PLoS One) - "Calcium-independent cathepsins do not contribute to RGC damage in monkey retinal explants cultured under hypoxia/reperfusion. In contrast, calcium influx from extracellular sources plays a critical role in inducing RGC damage. Elevated intracellular calcium levels could activate calpains, leading to RGC damage; however, other calcium-dependent pathways might also be involved in this process."

Journal • Preclinical • Glaucoma • Ophthalmology • Retinal Disorders • CAPN1 • CTSS

Hypoxia-Induced Activation of Calpain and Oxidative Stress in Mitochondria Leads to RGC Death in Human iPSC-derived Retinal Organoids. (PubMed, Exp Eye Res) - "Retinal organoids and purified RGCs were cultured with or without calcium chelator BAPTA, calpain inhibitor SNJ-1945, or NRF2 activator NK252 under hypoxia/reoxygenation...NK252 prevented RGC death but did not inhibit calpain-mediated proteolysis. Our findings with human iPS-drived RGC culture model demonstrate that calcium influx in hypoxic RGCs activates mitochondrial calpain, which induced the depletion of thiol levels and the collapse of MMP, ultimately leading to cell death."

Journal • Targeted Protein Degradation

Phase 2a study of calpain inhibitor SJP-0008 for central retinal artery occlusion (ARVO 2024) - "SJP showed clinically significant efficacy against non-arteritic CRAO, and no clinically relevant side effects were observed. SJP is expected to be put into practical use as an innovative treatment for CRAO, for which there is no effective treatment. Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand."

P2a data • Diabetic Retinopathy • Ophthalmology • Retinal Disorders

Activation of cytosolic and mitochondrial calpains during RGC death in hypoxic, human, iPS-derived retinal organoids (ARVO 2024) - "Retinal organoids and purified RGCs labeled with tdTomato were cultured with or without calcium chelator BAPTA or calpain inhibitor SNJ-1945 under hypoxia/reoxygenation... Calpain caused proteolysis of AIF in addition to structural proteins. This suggests that activated calpains in mitochondria as well as in cytosol could contribute to cell death in hypoxic RGCs. iPS-derived human retinal organoids and purified RGCs were useful in such studies on cell death mechanisms."

Ophthalmology • POU4F2

A novel combination approach to effectively reduce inflammation and neurodegeneration in multiple sclerosis models. (PubMed, Neurochem Int) - "A reduction in inflammatory T-cells with an increase in Tregs and myeloid suppressor cells is also found in EAE mice treated with SNJ1945 and 3aza-APL. Thus, a novel combination strategy was tested in chronic EAE mouse model in B10 mice which showed multiple pathological mechanisms could be addressed by simultaneous treatment with calpain inhibitor SNJ1945 and protease-resistant 3aza-APL to achieve a stronger therapeutic effect."

Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • MBP

GCL loss in BRAO. (PubMed, PLoS One) - "Measurement of GCL thickness would be a useful indicator of amelioration of BRAO and CRAO progression in a clinical trial of a putative inhibitor."

Journal • Ophthalmology • Retinal Disorders • Targeted Protein Degradation

Inhibition of endoplasmic reticulum stress and the downstream pathways protects CD4 T cells against apoptosis and immune dysregulation in sepsis. (PubMed, IUBMB Life) - "Our findings indicate that ER stress inhibitors may play a protective role by reducing CD4 T cell apoptosis and maintaining CD4 T cell function, which may be useful for enhancing the immune function and poor prognosis of patients with sepsis."

Journal • Infectious Disease • Septic Shock • ATF4 • ATF6 • CD4 • HSPA5 • IL10 • IL4 • IL6 • TNFA

Involvement of calpains and caspases in RGC damage in human iPSCs-derived OV cultured under hypoxia (ARVO 2022) - "When tested, caspase-8 (IETD) and caspase-9 (LEHD) inhibitors, and calpain inhibitor (SNJ1945) were added along with hypoxia... Calpains and caspases are involved in hypoxia/reoxygenation-induced damage to iPSCs-derived RGCs. Human iPSCs derived RGCs are useful for research where access to human eye tissues is limited."

Ophthalmology • CASP3 • CASP8 • CASP9