UCN2

Renova is exploring new therapeutic opportunities that have the potential to expand the use of Renova's gene therapy platform to include several pathologies associated with diabetes and heart failure. CARLSBAD, CA & SAN DIEGO, CA / ACCESSWIRE / June 12, 2024 / Renova Therapeutics, a biotechnology company developing gene therapy-based treatments for cardiovascular and metabolic diseases, announced today current and potential future clinical directions that can expand the use of its gene therapies to treat additional debilitating diseases. Renova is pushing ahead with its two most advanced therapies and is poised to launch a phase 2b/3 clinical trial for heart failure (HF) and a first-in-human trial for type 2 diabetes (T2DM) upon approval by regulatory agencies. In addition to its potential to treat type 2 diabetes as demonstrated in preclinical studies, Renova's Ucn2 gene therapy has potential therapeutic applications for type 1 diabetes, non-alcoholic fatty liver disease (NAFLD) (also known as metabolic dysfunction-associated steatotic liver disease (MASLD)), hypertension and heart failure. NAFLD Non-alcoholic fatty liver disease (NAFLD), for example, which is a common cause of liver failure in the U.S.,[1] was present in models of diabetes in the preclinical studies. Ucn2 gene transfer significantly reduced fatty infiltration six to eight weeks after a single intravenous delivery of the therapeutic product. Type 1 Diabetes Preclinical data demonstrated that a one-time intravenous injection of AAV8.Ucn2 has beneficial effects in a murine model of insulin deficiency analogous to type 1 diabetes. Beneficial effects included marked improvement in abnormal glucose flux, reduced retinopathy, and reduction in mortality from 94% to 18% (p<.0001). In addition, published preclinical studies have shown the usefulness of Ucn2 gene transfer in heart failure with reduced ejection fraction (EF) and heart failure with preserved EF. Renova received an NIH STTR Award to investigate the use of Ucn2 gene transfer for type 1 diabetes and associated left ventricular dysfunction. Hypertension Hypertension is a major risk factor for both heart failure, stroke and kidney failure leading to dialysis. In 2020, about half of U.S. adults - 122 million patients - had hypertension (high blood pressure).[2] Despite many anti-hypertensive drugs on the market, hypertension continues to contribute to the high incidence of these conditions. These data underscore the challenge of managing hypertension effectively, providing a rationale for gene therapy for this pervasive and difficult to treat disease. Preclinical studies are investigating the use of Ucn2 gene therapy for hypertension. Renova holds worldwide, exclusive licenses to key patents covering composition matters and delivery methods as well as clinical data. The Company intends to further develop its internal intellectual property (IP), acquire strategic IP, and utilize market exclusivity for its gene therapies granted by the regulatory agencies. "Despite the many therapies we now have for diabetes, we still see too many patients with inadequate blood sugar control and frequent complications of diabetes. Gene therapy is clearly one of the most promising new approaches to reducing the impact of diabetes," said Dr. David Horwitz (MD, PhD, MBA), member of Renova's Scientific Advisory Board. Dr. Horwitz previously served as Global Chief Medical Officer at the Johnson & Johnson Diabetes Institute and is a former member of the FDA advisory panel in clinical chemistry and toxicology. "Renova is privileged to have Dr. Horwitz as part of its Scientific Advisory Board. His expertise in health care and wealth of knowledge in metabolic diseases is a great asset to the Company in advancing its products and helping patients worldwide," said Renova CEO Dr. Vijay Mahant. About Renova Therapeutics Renova Therapeutics is developing definitive, one-time gene therapies to restore the health of people suffering from chronic diseases. The company is focusing on gene therapy treatments for heart failure and type 2 diabetes, two of the most common and devastating chronic diseases in the world. The company's lead product candidate, RT-100, is a treatment that delivers a therapeutic gene directly to the heart during a routine outpatient procedure and has the potential to increase heart function in millions of patients with heart failure. The Company's product pipeline also includes a groundbreaking gene therapy in preclinical stage for sufferers of type 2 diabetes. Renova Therapeutics was founded in 2009 and is led by an experienced management team in biopharmaceuticals and gene therapy. For additional information about the company, please visit . DISCLOSURE NOTICE: The information contained in this release is as of June 10, 2024. Renova Therapeutics assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments. Media and Investor Contact: +1 858.461.1837 info@renovatherapeutics.com [1] Cotter TG, Rinella M. Nonalcoholic Fatty Liver Disease 2020: The State of the Disease. Gastroenterology. 2020 May;158(7):1851-1864. doi: 10.1053/j.gastro.2020.01.052. Epub 2020 Feb 13. PMID: 32061595. [2] Martin et. al. 2024 Heart disease and stroke statistics: a report of U.S. and global data from the American Heart Association. Circulation. Published online January 24, 2024. doi: 10.1161/CIR.0000000000001209. Contact Information Vijay Mahant CEO info@renovatherapeutics.com 619-992-3260 SOURCE: Renova Therapeutics, Inc. View the original press release on newswire.com.

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.