UCN2

SHANGHAI, NANJING, China and SAN JOSE, Calif., Jan. 31, 2024 /PRNewswire/ -- On Jan. 30, 2024, PNAS published the research paper titled "Single-cell analysis of refractory anti-SRP necrotizing myopathy treated with anti-BCMA CAR T-cell therapy." The paper analyzed results using the fully human B cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR)-antologous T cell (BCMA CAR-T) injection (Equecabtagene Autoleucel injection, R&D code: CT103A) for the treatment of IMNM, which showed durable pathogenic antibody clearance, and potentially persistent clinical efficacy with good tolerability and safety. This study provides a potentially new therapeutic option for antibody-mediated autoimmune disorders. IMNM is an autoimmune-mediated skeletal muscle disorder belonging to an idiopathic inflammatory disease. IMNM mediated by human anti-signal recognition particle (SRP) antibody, an IMNM-specific autoantibody, is mainly characterized by symmetrical weakness of limb proximal muscles, prominent dysphagia, and significantly elevated serum creatine kinase, with features of acute onset, severe conditions, and rapid progression. Traditional pharmacological approaches have varying and often limited effects. This study is an investigator-initiated, open-label, exploratory clinical study to evaluate the safety and efficacy of infusion of Equecabtagene Autoleucel in the treatment of relapsed/refractory antibody-mediated idiopathic inflammatory diseases of the nervous system (NCT04561557). The investigator team is led by Professor Wang Wei from Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. A 25-year-old male patient with a 7-year history of SRP antibody-positive refractory IMNM was enrolled in this study. The patient had been subject to repeated relapses and persistent injuries even after receiving multiple prior therapies including steroids, calcineurin inhibitors, folic acid antagonists, CD20 monoclonal antibodies, interleukin-6 (IL-6) receptor antagonists, inosine monophosphate dehydrogenase (IMPDH) inhibitors, alkylating agents, plasmapheresis, intravenous immunoglobulin injection, and mesenchymal stem cell infusion. Before enrollment, the patient was still paralyzed and bedridden. He was not able to lift his arms overhead and his serum creatine kinase was up to 4806 IU/L (Normal range ≤ 190 U/L) even under regular combination therapies with steroids, IL-6 receptor antagonists, folic acid antagonists, and intravenous immunoglobulin injection. Safety: The patient developed only grade 1 cytokine release syndrome (CRS), but had no immune effector cell-associated neurotoxicity syndrome (ICANS). Only transient hemocytopenia was observed. No new safety risks were found compared to the safety profile in the studies of multiple myeloma indication. Efficacy: During the 18-month follow-up after infusion of Equecabtagene Autoleucel, the patient's clinical symptoms and imaging characteristics continuously improved. Three months after infusion of Equecabtagene Autoleucel, the patient's strength of extremities improved significantly. He could lift his arms without much effort, and regained his ability to walk. Manual Muscle Testing-8 (MMT-8) score improved from 96 points at baseline to 137 points at the last visit (18 months after infusion). Serum creatine kinase level decreased from 4778 IU/L before infusion to 260 IU/L at the last visit, and myoglobin level decreased from 837 ng/mL before infusion to 66.2 ng/mL at the last visit. Significant improvements were also observed in other quality of life scales. There was no concomitant use of other immunomodulatory therapies during the follow-up. PK/PD: The expansion of CAR-T cells in the patient was good after infusion of Equecabtagene Autoleucel. The serum SRP antibody level declined rapidly and remained at a very low level. The principal investigator of this study, Professor Wang Wei from Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology said: "This is the first time globally to apply BCMA CAR-T cell therapy to treat IMNM, which is another important breakthrough in the field of autoimmune diseases after the successful treatment of neuromyelitis optica spectrum disorders (NMOSD) with BCMA CAR-T. We look forward to the further development of CAR-T therapy in the field of autoimmunity, bringing hope of cure to patients." In addition to the research results published this time, IASO Bio and the investigator team are continuing to explore the safety and efficacy of Equecabtagene Autoleucel in the treatment of other autoimmune disorders including NMOSD, myasthenia gravis (MG), and chronic inflammatory demyelinating polyneuropathy (CIDP), for the hope of changing the treatment paradigm of autoimmune disorders. About IASO Bio IASO Bio is a biopharmaceutical company engaged in the discovery and development of novel cell therapies and biologics for oncology and autoimmune diseases. IASO Bio possesses comprehensive capabilities spanning the entire drug development process, from early discovery to clinical development, regulatory approval, and commercial production. The pipeline in the company includes a diversified portfolio of over 10 novel products, including Equecabtagene Autoleucel (a fully human BCMA CAR-T injection). Equecabtagene Autoleucel received New Drug Application (NDA) approval from China's National Medical Products Administration (NMPA) and U.S. FDA IND approval for the treatment of RR MM. Leveraging its strong management team, innovative product pipeline, GMP production, as well as integrated manufactural and clinical capabilities, IASO aims to deliver transformative, curable, and affordable therapies that fulfil unmet medical needs to patients in China as well as around the world. For more information, please visit or . SOURCE IASO Bio

Researchers have deciphered a biochemical mechanism that ensures that newly formed proteins are processed correctly when they leave the cell's own protein factories. This solves a decade-old puzzle in protein sorting. Based on genetic blueprints, individual amino acids are assembled into long amino acid chains, the proteins, in the protein factories of our cells, the ribosomes. Each newly formed protein starts with the amino acid methionine. This amino acid is often split off again during protein synthesis, as soon as the growing amino acid chain leaves the protein factory through the "ribosomal tunnel." In these cases, the excision of methionine is essential to ensure the subsequent function of the corresponding proteins in the cell. The enzymes causing this cleavage are already known. According to their function, they are called methionine aminopeptidases (METAPs). Up to now, it was unclear how METAPs come into contact with the protein factories and, just at the right place and moment, cause the excision of methionine from specific proteins. Biologists Elke Deuerling, Martin Gamerdinger and their team from the University of Konstanz (Germany), together with Nenad Ban and his colleagues from ETH Zurich (Switzerland), have now shed light on the subject. The results published in Science show: access of METAPs to protein factories is controlled by a "ribosomal gatekeeper" called NAC (short for "nascent polypeptide-associated complex"). More extensive function than previously known Only last year (2022), the team led by Deuerling and Gamerdinger was able to elucidate that NAC performs an important sorting function at the ribosomal tunnel: "We were able to show that NAC sits in front of the tunnel exit like a gatekeeper. There it controls the transport of proteins to the endoplasmic reticulum (ER) -- the membrane network inside the cell -- by specifically bringing together protein and transport molecule (SRP)," Deuerling summarizes the previous study results. In their new study, the researchers now show that the gatekeeper's sorting function is more extensive and even more significant than previously known, and that NAC also ensures the correct methionine excision from nascent proteins. In proteins transported to the ER, the first amino acid methionine is part of a transport signal. "Methionine excision in these proteins would destroy the signal and thus prevent its transport into the cell's membrane network, which would inevitably lead to cell death," Gamerdinger explains. How these transport signals are prevented from being destroyed by METAPs was a major scientific puzzle the scientists from Konstanz and Zurich have now solved: The gatekeeper NAC forms a complex with METAP1 and the ribosome at the exit of the ribosomal tunnel. Only within this complex can the enzyme cause the excision of methionine from newly formed proteins. This changes as soon as a protein with a transport signal leaves the ribosomal tunnel. Interactions between the protein's signal sequence and NAC then cause the gatekeeper to change its own position at the ribosomal tunnel. As a result, METAP1 loses its binding to NAC and thus its ability to cleave off methionine. With the changed position of the gatekeeper, a new binding interface becomes accessible for the transport molecule SRP. "This mechanism means that proteins lacking signal sequences can be specifically modified by methionine excision. Those, in contrast, that are transported to the endoplasmic reticulum, remain unaffected by METAP1," Gamerdinger explains. The gatekeeper as a mediation all-rounder? The researchers hypothesize that NAC may have other similar mediating functions at the ribosomal tunnel, thus assuming the role of a general molecular control centre. "There is a large number of enzymes and transport molecules that, like METAP1 and SRP, interact with the nascent proteins already during protein synthesis. Future studies will therefore have to show whether NAC also plays a role in regulating other processes that are vital for the function of our cells," says Deuerling.

Statistically significant decreased levels of novel biomarker AGO2 (p= 0.002) observed in newly diagnosed people living with Parkinson's disease (PD) compared to healthy individuals NeuroSense's combination platform has been observed in a clinical trial to induce an increase of AGO2 in ALS patients, indicating therapeutic potential in PD NeuroSense is exploring co-development of PD asset with potential collaborators CAMBRIDGE, Mass., May 2, 2023 /PRNewswire/ -- NeuroSense Therapeutics Ltd. (Nasdaq: NRSN) ("NeuroSense"), a company developing treatments for severe neurodegenerative diseases, today announced positive preliminary results from a novel biomarker study conducted to evaluate the potential of NeuroSense's combination platform therapy for the treatment of Parkinson's disease (PD), the second most common neurodegenerative disorder. This study compared blood samples from 30 healthy individuals to 30 people living with PD by utilizing neuronal derived exosomes to identify modulations in PD-associated biomarkers, including AG02. AGO2 (Argonaute 2), the catalytic subunit of the protein complex responsible for RNA-induced silencing,1 was shown to be critical to the regulation of alpha-synuclein (αSyn) accumulation in dopaminergic neurons of the substantia nigra pars compacta, the region of the brain that is responsible for motor control.2 The dysregulation of αSyn through dysfunction of AGO2 can have detrimental effects in the brain, which can lead to PD. In the PD biomarker study, NeuroSense observed a statistically significant (p= 0.002) decrease in levels of AGO2 in newly diagnosed PD patients (n=15) when compared to the healthy control group. There were no significant changes observed in AGO2 levels of more advanced stage PD patients, indicating this trend could be related to disease onset. In a Phase 2a clinical trial conducted in people living with amyotrophic lateral sclerosis (ALS), NeuroSense's platform combination therapy was observed to induce a statistically significant (p= 0.039) increase of AGO2 and also showed a trend of increased levels of LC3 (p= 0.054). LC3 is an essential protein involved in autophagy,3 a cellular recycling process utilized to degrade aggregated proteins and damaged organelles, which has been reported to be involved in many neurodegenerative disorders, including PD. In the PD biomarker study NeuroSense observed a change in levels of LC3, which decreased in newly diagnosed PD patients (p= 0.034), suggesting an impairment in cellular recycling processes. Other biomarkers that were measured, including some PD-specific markers, did not reveal trends and may be revisited in future studies. "We believe these results strengthen the scientific rationale to develop NeuroSense's platform technology for PD, as the mechanism of action may be helpful in targeting disease-specific pathways, specifically AGO2 dysregulation," stated Dr. Shiran Zimri, NeuroSense's VP of R&D. "We intend to further evaluate these findings, as well as explore additional biomarkers and their involvement in the progression and pathology of PD in future studies." Prof. Roy Alcalay M.D., Chief of the Movement Disorders Center at Tel-Aviv Sourasky Medical Center, who participated in conducting the PD biomarker study, commented, "We are excited by this interesting collaboration and look forward to continuing our work together." "We believe that these data denote the potential of NeuroSense's platform technology to target early stages of Parkinson's disease. This is particularly relevant as early detection of PD is becoming more common," stated NeuroSense's CEO, Alon Ben-Noon. "Based on these encouraging results, we are now looking to co-develop our PD asset with collaborators that have a core focus on Parkinson's." About Parkinson's Disease Parkinson's disease (PD) is the second most common neurogenerative condition after Alzheimer's disease. Nearly 1 million people in the U.S. and an estimated 10 million people worldwide are living with PD. Characterized by uncontrollable movements, difficulty with balance and coordination, as well fatigue, depression, and memory difficulties, these symptoms begin to occur when dopaminergic neurons in the substantia nigra become impaired and die. The global PD treatment market was valued at $5.7 billion in 2021 and is projected to reach $10.4 billion by 2031, growing at a CAGR of 6.2%. About AGO2 AGO2 is a protein-coding gene essential for miRNA function. It is involved in the regulation of alpha-synuclein (αSyn) biogenesis. As obtained in cultures and cell tissues alike, depletion of AGO2 leads to αSyn accumulation. In pre-clinical studies, an increase in αSyn mRNA and protein expression was observed when AGO2 is knocked-out. The dysregulation of αSyn through dysfunction of AGO2 can have detrimental effects in the brain, resulting in PD.2 About LC3 LC3, microtubule-associated protein 1A/1B-light chain 3, is an essential protein involved in autophagosome biogenesis/maturation, as well as an adaptor protein for selective autophagy.3 The most prevalent pathological features of many neurodegenerative diseases are the aggregation of misfolded proteins and the loss of neurons. Autophagy, utilized to degrade aggregated proteins and damaged organelles, has been reported to be involved in the occurrence of pathological changes in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS).4Therefore, LC3 has been widely used to monitor the number of autophagosomes as well as autophagic activity.3 About NDEs NeuroSense's biomarker study utilized neuronal-derived exosomes (NDEs) extracted from plasma. NDEs are small extracellular vesicles (EVs) generated by neurons that encapsulate a variety of molecules such as proteins, nucleic acids, and metabolites. ExoSORT™ by NeuroDex was used to identify NDEs in this biomarker study. Identification of NDEs and their cargo in body fluids can facilitate the discovery of new biomarkers for prognosis and therapy, as these vesicles can pass the blood-brain barrier (BBB) and provide a depiction of the current physiological status of neurons in the brain. About NeuroSense NeuroSense Therapeutics, Ltd. is a clinical-stage biotechnology company focused on discovering and developing treatments for patients suffering from debilitating neurodegenerative diseases. NeuroSense believes that these diseases, which include amyotrophic lateral sclerosis (ALS), Alzheimer's disease and Parkinson's disease, among others, represent one of the most significant unmet medical needs of our time, with limited effective therapeutic options available for patients to date. Due to the complexity of neurodegenerative diseases and based on strong scientific research on a large panel of related biomarkers, NeuroSense's strategy is to develop combined therapies targeting multiple pathways associated with these diseases. For additional information, we invite you to visit our website and follow us on LinkedIn and Twitter. Forward-Looking Statements This press release contains "forward-looking statements" that are subject to substantial risks and uncertainties. All statements, other than statements of historical fact, contained in this press release are forward-looking statements. Forward-looking statements contained in this press release may be identified by the use of words such as "anticipate," "believe," "contemplate," "could," "estimate," "expect," "intend," "seek," "may," "might," "plan," "potential," "predict," "project," "target," "aim," "should," "will" "would," or the negative of these words or other similar expressions, although not all forward-looking statements contain these words. Forward-looking statements are based on NeuroSense Therapeutics' current expectations and are subject to inherent uncertainties, risks and assumptions that are difficult to predict and include statements regarding the co-development of our PD assets with collaborators with a core focus on Parkinson's. Further, certain forward-looking statements are based on assumptions as to future events that may not prove to be accurate. Forward-looking statements are subject to a number of risks and uncertainties, including a delay in the reporting of top-line results from our ALS Phase 2b clinical trial, the risk that the final results of Parkinson's Disease (PD) Biomarker Study will not be consistent with the preliminary results and the risk that we will not be successful in signing co-development agreement or other agreements with collaborators with a core focus on Parkinson's. The future events and trends may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward looking statements. You should not rely on these statements as representing our views in the future. More information about the risks and uncertainties affecting the Company is contained under the heading "Risk Factors" in the Annual Report on Form 20-F filed with the Securities and Exchange Commission on March 22, 2023. Forward-looking statements contained in this announcement are made as of this date, and NeuroSense Therapeutics Ltd. undertakes no duty to update such information except as required under applicable law. 1 O'Carroll, D. & Schaefer, A. General Principals of miRNA Biogenesis and Regulation in the Brain. Neuropsychopharmacology 38, 39-54, doi:10.1038/npp.2012.87 (2013). 2 Hernandez, S. M. et al. Unexpected Implication of SRP and AGO2 in Parkinson's Disease: Involvement in Alpha-Synuclein Biogenesis. Cells 10, doi:10.3390/cells10102792 (2021). 3 Lee, Y. K. & Lee, J. A. Role of the mammalian ATG8/LC3 family in autophagy: differential and compensatory roles in the spatiotemporal regulation of autophagy. BMB reports 49, 424-430, doi:10.5483/bmbrep.2016.49.8.081 (2016). 4 Guo, F., Liu, X., Cai, H. & Le, W. Autophagy in neurodegenerative diseases: pathogenesis and therapy. Brain pathology (Zurich, Switzerland) 28, 3-13, doi:10.1111/bpa.12545 (2018). Company Codes: NASDAQ-NMS:NRSN