作者: Shaw, Robin M ; Richmond, Bradley ; Cluntun, Ahmad A ; Hong, TingTing ; Funai, Katsuhiko ; Symons, J David ; Shaw, Kikuyo ; Li, Jing ; Bia, Ryan ; Franklin, Sarah ; Walsh, Maureen A ; Rutter, Jared

Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intracardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes-induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium-handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalized components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalized insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescued cardiac lusitropy, improved exercise intolerance, and ameliorated hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy and can also improve systemic glycemic control.

2022-01-01·Theranostics

Subpial delivery of adeno-associated virus 9-synapsin-caveolin-1 (AAV9-SynCav1) preserves motor neuron and neuromuscular junction morphology, motor function, delays disease onset, and extends survival in hSOD1^G93A mice

Article

作者: Wang, Shanshan ; Ichinomiya, Taiga ; Patel, Piyush M ; Li, Xiaojing ; Savchenko, Paul ; Wang, Dongsheng ; Head, Brian P ; Duong, Tiffany ; Miyanohara, Atsushi ; Li, Wenxi ; Marsala, Martin ; Bonds, Jacqueline A ; Kim, Eun Jung ; Sawada, Atsushi ; Patel, Hemal H ; Roth, David M ; Tadokoro, Takahiro

Elevating neuroprotective proteins using adeno-associated virus (AAV)-mediated gene delivery shows great promise in combating devastating neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is one such disease resulting from loss of upper and lower motor neurons (MNs) with 90-95% of cases sporadic (SALS) in nature. Due to the unknown etiology of SALS, interventions that afford neuronal protection and preservation are urgently needed. Caveolin-1 (Cav-1), a membrane/lipid rafts (MLRs) scaffolding and neuroprotective protein, and MLR-associated signaling components are decreased in degenerating neurons in postmortem human brains. We previously showed that, when crossing our SynCav1 transgenic mouse (TG) with the mutant human superoxide dismutase 1 (hSOD1^G93A) mouse model of ALS, the double transgenic mouse (SynCav1 TG/hSOD1^G93A) exhibited better motor function and longer survival. The objective of the current study was to test whether neuron-targeted Cav-1 upregulation in the spinal cord using AAV9-SynCav1 could improve motor function and extend longevity in mutant humanized mouse and rat (hSOD1^G93A) models of familial (F)ALS. Methods: Motor function was assessed by voluntary running wheel (RW) in mice and forelimb grip strength (GS) and motor evoked potentials (MEP) in rats. Immunofluorescence (IF) microscopy for choline acetyltransferase (ChAT) was used to assess MN morphology. Neuromuscular junctions (NMJs) were measured by bungarotoxin-a (Btx-a) and synaptophysin IF. Body weight (BW) was measured weekly, and the survival curve was determined by Kaplan-Meier analysis. Results: Following subpial gene delivery to the lumbar spinal cord, male and female hSOD1G93A mice treated with SynCav1 exhibited delayed disease onset, greater running-wheel performance, preserved spinal alpha-motor neuron morphology and NMJ integrity, and 10% increased longevity, independent of affecting expression of the mutant hSOD1G93A protein. Cervical subpial SynCav1 delivery to hSOD1G93A rats preserved forelimb GS and MEPs in the brachial and gastrocnemius muscles. Conclusion: In summary, subpial delivery of SynCav1 protects and preserves spinal motor neurons, and extends longevity in a familial mouse model of ALS without reducing the toxic monogenic component. Furthermore, subpial SynCav1 delivery preserved neuromuscular function in a rat model of FALS. The latter findings strongly indicate the therapeutic applicability of SynCav1 to treat ALS attributed to monogenic (FALS) and potentially in sporadic cases (i.e., SALS).

2021-12-01·Pacing and Clinical Electrophysiology3区 · 工程技术

Improvement of electrical synchrony in cardiac resynchronization therapy using dynamic atrioventricular delay programming and multipoint pacing

3区 · 工程技术

Article

作者: Lemke, Bernd ; Schiedat, Fabian ; Mügge, Andreas ; Karosiene, Zana ; Zarse, Markus ; Kloppe, Axel ; Hanefeld, Christoph ; Bogossian, Harilaos ; Mijic, Dejan

AbstractBackgroundOptimization of cardiac resynchronization therapy (CRT) is often time‐consuming and therefore underused in a clinical setting. Novel device‐based algorithms aiming to simplify optimization include a dynamic atrioventricular delay (AVD) algorithm (SyncAV, Abbott) and multipoint pacing (MPP, Abbott). This study examines the acute effect of SyncAV and MPP on electrical synchrony in patients with newly and chronically implanted CRT devices.MethodsPatients with SyncAV and MPP enabled devices were prospectively enrolled during implant or scheduled follow‐up. Blinded 12‐lead electrocardiographic acute measurements of QRS duration (QRSd) were performed for intrinsic QRSd (Intrinsic), bi‐ventricular pacing (BiV), MPP, BiV with SyncAV at default offset 50 ms (BiVSyncAVdef), BiV with SyncAV at patient‐specific optimised offset (BiVSyncAVopt), MPP with SyncAV at default offset 50 ms (MPPSyncAVdef), and MPP with SyncAV at patient‐specific optimised offset (MPPSyncAVopt).ResultsThirty‐three patients were enrolled. QRSd for Intrinsic, BiV, MPP, BiVSyncAVdef, BiVSyncAVopt, MPPSyncAVdef, MPPSyncAVopt were 160.4 ± 20.6 ms, 141.0 ± 20.5 ms, 130.2 ± 17.2 ms, 121.7 ± 20.9 ms, 117.0 ± 19.0 ms, 121.2 ± 17.1 ms, 108.7 ± 16.5 ms respectively. MPPSyncAVopt led to greatest reduction of QRSd relative to Intrinsic (−31.6 ± 11.1%; p < .001), showed significantly shorter QRSd compared to all other pacing configurations (p < .001) and shortest QRSd in every patient. Shortening of QRSd was not significantly different between newly and chronically implanted devices (−51.6 ± 14.7 ms vs. −52.7 ± 21.9 ms; p = .99).ConclusionSyncAV and MPP improved acute electrical synchrony in CRT. Combining both technologies with patient‐specific optimization resulted in greatest improvement, regardless of time since implantation.Whats newNovel device‐based algorithms like a dynamic AVD algorithm (SyncAV, Abbott) and multipoint pacing (MPP, Abbott) aim to simplify CRT optimization. Our data show that a combination of patient tailored SyncAV optimization and MPP results in greatest improvement of electrical synchrony in CRT measured by QRS duration, regardless if programmed in newly or chronically implanted devices. This is the first study to our knowledge to examine a combination of these device‐based algorithms. The results help understanding the ideal ventricular excitation in heart failure.

项与 SynCav-1 相关的新闻（医药）

2024-11-13

·PRNewswire

75+ Key Companies Charting New Frontiers in Multiple Sclerosis Therapeutic Space | DelveInsight

Multiple sclerosis (MS) is a chronic neurological disorder affecting the central nervous system (CNS), particularly the brain, spinal cord, and optic nerves. Continuous research has led to new drug developments, particularly disease-modifying therapies (DMTs) that slow MS progression. Monoclonal antibodies, oral therapies, and infusion treatments are among the most promising options and drives the multiple sclerosis market. LAS VEGAS, Nov. 13, 2024 /PRNewswire/ -- DelveInsight's ' Multiple Sclerosis Pipeline Insight 2024 ' report provides comprehensive global coverage of pipeline multiple sclerosis therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the multiple sclerosis pipeline domain. Key Takeaways from the Multiple Sclerosis Pipeline Report DelveInsight's multiple sclerosis pipeline report depicts a robust space with 75+ active players working to develop 80+ pipeline therapies for multiple sclerosis treatment. Key multiple sclerosis companies such as Mapi Pharma, Novartis, Immunic, Biocad, Apimeds, Genentech (Roche), AB Science, Celltrion, Clene Nanomedicine, InnoCare Pharma, Oryzon Genomics, GeNeuro SA, AbbVie, BrainStorm Cell Therapeutics, NeuroSense Therapeutics, Denali Therapeutics Inc., Sanofi, MediciNova, Biogen, Tiziana Life Sciences, Antisense Therapeutics, RemeGen, Atara Biotherapeutics, Contineum Therapeutics, Eli Lilly and Company, Axsome Therapeutics, Accure therapeutics, Stem Cell Medicine Ltd., Ever Supreme Bio-Technology Co., Ltd., ImCyse, Lucid Psycheceuticals, Immune Response BioPharma, Guangzhou Lupeng Pharmaceutical, Kyowa Kirin, Nura Bio, Bristol-Myers Squibb, ImStem Biotechnology, Hoffmann-La Roche, LAPIX Therapeutics, Motric Bio, Immunophage Biotech, NervGen, FibroBiologics, Kyverna Therapeutics, GlaxoSmithKline, PolTREG, Cyxone, Biohaven Pharmaceuticals, HuniLife Biotechnology, GlobeStar Therapeutics, Anokion, Medsenic, ZyVersa Therapeutics, Alumis Inc., Axoltis Pharma, Barricade Therapeutics, BioNxt Solutions, Eikonoklastes Therapeutics, 4D Pharma, Gossamer Bio, Pasithea Therapeutics, Synaptogenix, Monte Rosa Therapeutics, Immix Biopharma, f5 Therapeutics, Autobahn Therapeutics, Biosenic, Polpharma Biologics, Find Therapeutics, TeraImmun, AptaTargets, Trethera, Aditxt, SetPoint Medical, Sarepta Therapeutics, Nucleome Therapeutics, Vaccinex Inc., and others are evaluating new multiple sclerosis drugs to improve the treatment landscape. Promising multiple sclerosis pipeline therapies such as GA Depot, Remibrutinib, Tolebrutinib, IMU 838, BCD-132, Apitox, Fenebrutinib, SAR 441344, CT-P53, CNM-Au8, Orelabrutinib, Vafidemstat, Temelimab, Elezanumab, NurOwn (MSC-NTF cells), PrimeC, SAR4433820, Ibudilast, BIIB091, Foralumab, ATL1102, RC18, ATA188, PIPE-307, Pirtobrutinib, LY3541860, Solriamfetol, Act-01, SCM-010, UMSC01, IMCY-0141, Lucid-MS, NeuroVax, LP-168, NB-4746, CC-97540, IMS-001, RO7121932, BMS-986196, LPX-TI641, MTR-601, IPG-11406, IPG-1094, NVG-291, CYMS-101, KYV-101, PIPE-791, GSK 3888130B, PTG-007, T 20K, BHV-8000, HuL001, Amethyst™, ANK 700, Arscimed, A-005, NX210c, Research programme: CAR-TREG, TASIN-1, Cladribine ODF, ET-101, MRx0002, GB7208, PAS-002, Bryostatin-1, MRT-6160, NXC-201, Research Program: Cytokine reduction, ABX-002, Arsenic trioxide, LL-341070, PB018, FTX 101, TI-235, TRE 515, NT-0007, NT-0002, NVG300, and others are under different phases of multiple sclerosis clinical trials. In October 2024, Immunic, Inc. reported favorable results from the non-binding interim futility analysis of its Phase 3 ENSURE trial, which is evaluating its lead candidate, vidofludimus calcium (IMU-838), a nuclear receptor-related 1 (Nurr1) activator, for the treatment of relapsing multiple sclerosis (RMS). In October 2024, Immunic, Inc. announced a positive outcome of the non-binding, interim futility analysis of its Phase III ENSURE program, investigating lead asset, nuclear receptor related 1 (Nurr1) activator, vidofludimus calcium (IMU-838), for the treatment of relapsing multiple sclerosis (RMS). Based on the outcome of the interim futility analysis, an unblinded Independent Data Monitoring Committee (IDMC) has recommended that the trials are not futile and should continue as planned. In September 2024, Roche, secured FDA approval for an injectable form of its blockbuster multiple sclerosis treatment, Ocrevus, reducing patient treatment time and potentially helping the company stay ahead of increasing competition. In September 2024, Sanofi announced the outcomes of Phase III clinical trials of its investigational oral brain-penetrant BTK inhibitor, tolebrutinib, aimed at treating multiple sclerosis (MS). These studies, namely HERCULES, GEMINI 1, and GEMINI 2, have provided mixed results, with the HERCULES trial meeting its primary endpoint while the GEMINI trials did not. The HERCULES study focused on the efficacy and safety of tolebrutinib in individuals with non-relapsing secondary progressive MS (nrSPMS) compared to a placebo. In August 2024, Abata Therapeutics announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for ABA-101 for the treatment of patients with progressive multiple sclerosis (MS). The FDA recently cleared ABA-101's Investigational New Drug (IND) application, and initiation of a first-in-human (FIH) Phase I study is imminent. In August 2024, TG Therapeutics announced that the FDA has cleared an investigational new drug (IND) application submitted by TG Therapeutics for azercabtagene zapreleucel (azer-cel), an investigational allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, for a phase 1 clinical trial in patients with progressive multiple sclerosis (MS). In January 2024, Kyverna Therapeutics, Inc. announced it received fast-track designation by the U.S. Food and Drug Administration (FDA) for its autologous, fully human CD19 chimeric antigen receptor (CAR) T-cell product candidate, KYV-101, to be used for the treatment of multiple sclerosis (MS). Request a sample and discover the recent advances in multiple sclerosis treatment drugs @ Multiple Sclerosis Pipeline Report The multiple sclerosis pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage multiple sclerosis drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the multiple sclerosis clinical trial landscape. Multiple Sclerosis Overview Multiple sclerosis is a chronic autoimmune disorder that affects the central nervous system, leading to the deterioration or permanent damage of myelin, the protective sheath surrounding nerve fibers. While the exact cause of multiple sclerosis remains unclear, it is believed to involve a combination of genetic predisposition, environmental factors, and possibly viral infections. Common symptoms of multiple sclerosis include fatigue, difficulty walking, numbness or tingling in the limbs, muscle weakness, and vision problems, which can vary significantly among individuals and may evolve over time. Diagnosis typically involves a combination of neurological examinations, magnetic resonance imaging (MRI) to detect lesions in the brain and spinal cord, and sometimes lumbar puncture to analyze cerebrospinal fluid for inflammatory markers. While there is no cure for multiple sclerosis, treatment options aim to manage symptoms, reduce the frequency and severity of relapses, and slow disease progression. This may include disease-modifying therapies (DMTs), corticosteroids for acute exacerbations, and symptomatic treatments such as physical therapy, pain management, and lifestyle modifications. Early diagnosis and a tailored treatment plan are crucial for improving the quality of life for those living with multiple sclerosis. Find out more about multiple sclerosis treatment drugs @ Drugs for Multiple Sclerosis Treatment A snapshot of the Multiple Sclerosis Pipeline Drugs mentioned in the report: Learn more about the emerging multiple sclerosis pipeline therapies @ Multiple Sclerosis Clinical Trials Multiple Sclerosis Therapeutics Assessment The multiple sclerosis pipeline report proffers an integral view of the multiple sclerosis emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Multiple Sclerosis Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Oral, Intravenous, Subcutaneous, Parenteral, Topical Therapeutics Assessment By Molecule Type: Recombinant fusion proteins, Small molecule, Monoclonal antibody, Peptide, Polymer, Gene therapy Therapeutics Assessment By Mechanism of Action: Immunomodulators, MHC class II gene modulators, Agammaglobulinaemia tyrosine kinase inhibitors, Dihydroorotate dehydrogenase inhibitors, Nuclear receptor subfamily 4 group A member 2 agonists, CD20 antigen inhibitors, Energy metabolism stimulants; Immunomodulators, Lysine-specific demethylase 1 inhibitors, Monoamine oxidase B inhibitors, Protein-arginine deiminase inhibitors, Immunostimulants Key Multiple Sclerosis Companies: Mapi Pharma, Novartis, Immunic, Biocad, Apimeds, Genentech (Roche), AB Science, Celltrion, Clene Nanomedicine, InnoCare Pharma, Oryzon Genomics, GeNeuro SA, AbbVie, BrainStorm Cell Therapeutics, NeuroSense Therapeutics, Denali Therapeutics Inc., Sanofi, MediciNova, Biogen, Tiziana Life Sciences, Antisense Therapeutics, RemeGen, Atara Biotherapeutics, Contineum Therapeutics, Eli Lilly and Company, Axsome Therapeutics, Accure therapeutics, Stem Cell Medicine Ltd., Ever Supreme Bio-Technology Co., Ltd., ImCyse, Lucid Psycheceuticals, Immune Response BioPharma, Guangzhou Lupeng Pharmaceutical, Kyowa Kirin, Nura Bio, Bristol-Myers Squibb, ImStem Biotechnology, Hoffmann-La Roche, LAPIX Therapeutics, Motric Bio, Immunophage Biotech, NervGen, FibroBiologics, Kyverna Therapeutics, GlaxoSmithKline, PolTREG, Cyxone, Biohaven Pharmaceuticals, HuniLife Biotechnology, GlobeStar Therapeutics, Anokion, Medsenic, ZyVersa Therapeutics, Alumis Inc., Axoltis Pharma, Barricade Therapeutics, BioNxt Solutions, Eikonoklastes Therapeutics, 4D Pharma, Gossamer Bio, Pasithea Therapeutics, Synaptogenix, Monte Rosa Therapeutics, Immix Biopharma, f5 Therapeutics, Autobahn Therapeutics, Biosenic, Polpharma Biologics, Find Therapeutics, TeraImmun, AptaTargets, Trethera, Aditxt, SetPoint Medical, Sarepta Therapeutics, Nucleome Therapeutics, Vaccinex Inc., and others are evaluating new multiple sclerosis drugs to improve the treatment landscape. Key Multiple Sclerosis Pipeline Therapies:GA Depot, Remibrutinib, Tolebrutinib, IMU 838, BCD-132, Apitox, Fenebrutinib, SAR 441344, CT-P53, CNM-Au8, Orelabrutinib, Vafidemstat, Temelimab, Elezanumab, NurOwn (MSC-NTF cells), PrimeC, SAR4433820, Ibudilast, BIIB091, Foralumab, ATL1102, RC18, ATA188, PIPE-307, Pirtobrutinib, LY3541860, Solriamfetol, Act-01, SCM-010, UMSC01, IMCY-0141, Lucid-MS, NeuroVax, LP-168, NB-4746, CC-97540, IMS-001, RO7121932, BMS-986196, LPX-TI641, MTR-601, IPG-11406, IPG-1094, NVG-291, CYMS-101, KYV-101, PIPE-791, GSK 3888130B, PTG-007, T 20K, BHV-8000, HuL001, Amethyst™, ANK 700, Arscimed, A-005, NX210c, Research programme: CAR-TREG, TASIN-1, Cladribine ODF, ET-101, MRx0002, GB7208, PAS-002, Bryostatin-1, MRT-6160, NXC-201, Research Program: Cytokine reduction, ABX-002, Arsenic trioxide, LL-341070, PB018, FTX 101, TI-235, TRE 515, NT-0007, NT-0002, NVG300, and others are under different phases of multiple sclerosis clinical trials. Dive deep into rich insights for new drugs for multiple sclerosis treatment, visit @ Multiple Sclerosis Drugs Table of Contents For further information on the multiple sclerosis pipeline therapeutics, reach out @ Multiple Sclerosis Treatment Drugs Related Reports Multiple Sclerosis Market Multiple Sclerosis Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key multiple sclerosis companies including Immune Response BioPharma, Inc., Clene Nanomedicine, Genzyme, ImStem Biotechnology, Rho, Inc., Bristol-Myers Squibb, TG Therapeutics, Inc., Hoffmann-La Roche, Atara Biotherapeutics, Immunic AG, Celgene, Anokion SA, Sanofi, Actelion, Biogen, Supernus Pharmaceuticals, Inc., GeNeuro SA, HuniLife Biotechnology, Inc., Emerald Health Pharmaceuticals, RemeGen Co., Ltd., Antisense Therapeutics, Biocad, AB Science, Genentech, Novartis, Pipeline Therapeutics, ASLAN Pharmaceuticals, GlaxoSmithKline, Lucid Psycheceuticals, Voronoi, Hanmi Pharmaceutical, Mapi Pharma, f5 Therapeutics, Autobahn Therapeutics, AstraZeneca, ZyVersa Therapeutics, RedHill Biopharma, Gossamer Bio, Sarepta Therapeutics, BrainStorm Cell Limited, CytoDyn, Pear Therapeutics, Solstice Neurosciences, ProJenX, among others. Multiple Sclerosis Epidemiology Forecast Multiple Sclerosis Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted multiple sclerosis epidemiology in the 7MM, i.e., the United States, EU5 (Germany, Spain, Italy, France, and the United Kingdom), and Japan. Relapsing Multiple Sclerosis Pipeline Relapsing Multiple Sclerosis Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key relapsing multiple sclerosis companies, including ASLAN Pharmaceuticals, GlaxoSmithKline, Lucid Psycheceuticals, Voronoi, Hanmi Pharmaceutical, among others. Relapsing-Remitting Multiple Sclerosis Pipeline Relapsing-Remitting Multiple Sclerosis Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key RRMS companies, including TG Therapeutics, Novartis, Sanofi, Cinnagen, Polpharma Biologics, Immunic, Mapi Pharma, Biocad, Apimeds, Genentech (Roche), Merck, Immune Response BioPharma, Clene Nanomedicine, InnoCare Pharma, Oryzon Genomics, GeNeuro SA, AbbVie, Emerald Health Pharmaceuticals, GlaxoSmithKline, RedHill Biopharma, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床3期临床结果快速通道细胞疗法免疫疗法

2023-05-15

·BioSpace

Eikonoklastes Announces Formation of Scientific Advisory Board – Gene Therapy

CINCINNATI--(BUSINESS WIRE)-- Eikonoklastes Therapeutics, a biopharmaceutical company developing a novel gene therapy platform to discover and develop critical treatments for Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases, today announced the formation of a Scientific Advisory Board (SAB) - Gene Therapy, comprised of key leaders in neurology and gene therapy development. The SAB – Gene Therapy will work cohesively with management to advance the company’s gene therapy pipeline. Eikonoklastes’s gene therapy platform is built upon the pioneering work from the lab of Dr. Brian Head, Professor of Anesthesiology at University of California, San Diego. “I am very pleased to join Eikonoklastes’ Scientific Advisory Board,” said Dame Pamela Shaw, DBE, MD. “I look forward to working with this distinguished group of industry experts to advise the Eikonoklastes team through the development of its innovative technology to address enormous unmet clinical needs.” “We are fortunate to have the support of a truly world-class group of scientific and industry thought leaders on our Scientific Advisory Board, who will offer their expertise to ensure we optimally design our development program to meet the needs of patients and rapidly advance this technology through regulatory approval to treat patients with this devastating disease,” said Bruce Halpryn, Ph.D., Board Chair and CEO of Eikonoklastes. “Each member brings unique experience in technology, manufacturing, regulatory affairs, and clinical development. This collection of unparalleled expertise will serve us well as we develop our lead candidate, ET-101, initially for ALS and expanding into several other inadequately treated neurodegenerative diseases,” said Samuel Lee, MD, MBA, MPH, President and Chief Business Officer of Eikonoklastes. The founding members of the Eikonoklastes Scientific Advisory Board – Gene Therapy are: Brian Head, PhD Research Career Scientist, VA San Diego Healthcare System Professor of Anesthesiology, University of California – San Diego Russell Lonser, MD Chairman, Department of Neurological Surgery, Ohio State University Wexner Medical Center Director, Gene Therapy Institute, Ohio State University Professor of Neuroscience, Ohio State University College of Medicine Michael O’Beirne Former Executive Director, Regulatory Strategy at Sarepta Therapeutics Vaithianathan “Palani” Palaniappan, PhD Chief Technology Officer, Pioneering Medicines at Flagship Pioneering Former Head of Global Technical Operations, Sarepta Former Global Head of Biologics and New Modality Development, Takeda Seward Rutkove, MD Chair, Department of Neurology at Beth Israel Deaconess Medical Center Professor of Neurology, Harvard Medical School Dame Pamela Shaw, DBE, MD Founder and Director, Sheffield Institute for Translational Neuroscience Professor of Neurology, University of Sheffield Mark Tuszynski, MD, PhD Director, UC San Diego Translational Neuroscience Institute Distinguished Professor of Neuroscience, University of California – San Diego About Eikonoklastes Therapeutics Eikonoklastes Therapeutics is a biotech company rapidly developing a pipeline of disruptive new treatments for today’s most challenging diseases. The company’s 1st-in-class gene therapy (ET-101) has been engineered to overexpress Caveolin-1, which organizes and regulates synaptic receptors essential for neuromuscular signaling and function. Eikonoklastes is also advancing a new generation of tissue factor (TF) therapies (ET-201) for the treatment of Triple Negative Breast Cancer and other oncology indications. To learn more, visit

基因疗法

2023-05-12

·药渡Daily

渐冻症治疗再添新成员，干细胞、基因治疗等多种新疗法前途可期

关键词肌萎缩侧索硬化症；Qalsody；研究进展肌萎缩侧索硬化症（ALS），俗称“渐冻症”，是一种渐进和致命的神经退行性疾病，由来自大脑和脊髓的运动神经元缺失引起，可导致四肢、躯干、胸部、腹部肌肉逐渐无力并萎缩，从而影响运动、交流、吞咽和呼吸功能，最终致死。据统计，全球范围内每10000人中大约有6-9个ALS患者，且患病率逐年增长。目前，ALS发病机制并不十分明确。据2023年3月英国谢菲尔德大学谢菲尔德转化神经科学研究所Pamela J. Shaw团队在Nature Reviews Drug Discovery期刊上发表的文章，ALS发病与遗传、氧化应激、兴奋性毒性、神经炎症反应、线粒体功能紊乱、DNA和RNA损伤、蛋白稳态受损、轴突损伤等有关，这些因素相互作用导致患者出现运动神经元损伤。复杂的发病机制导致ALS药物研发十分困难，目前全球获批治疗ALS的药物非常有限，已获批的药物包括利鲁唑、依达拉奉、Relyvrio和Qalsody。利鲁唑是是第一个获FDA和欧盟批准用于治疗ALS的药物。作为神经保护剂，利鲁唑可改善病人生存状态，但却无法阻止ALS病情的发展，目前已获批的剂型包括片剂、口腔膜剂和混悬剂。依达拉奉是一种脑保护剂（自由基清除剂），为期6个月的临床试验证明其能够减缓ALS相关的日常功能衰退。目前，已获批的剂型有静脉注射剂（如Radicava）和口服混悬剂（如Radicava ORS）。Relyvrio是苯丁酸钠(PB)和牛磺酸二醇(TURSO)组成的复方制剂，其靶向ALS和其他神经退行性疾病中的内质网和线粒体依赖性神经元退行性变通路，减少神经元死亡和功能障碍，可显著减缓ALS疾病进展和延长生存期。2022年，Relyvrio先后在加拿大和美国被批准用于治疗成人ALS。Qalsody（tofersen）是Ionis研发的一种反义寡核苷酸（ASO)药物，它能够与编码SOD1的 mRNA结合，被核糖核酸酶RNase-H降解，从而减少突变SOD1蛋白的生成。2023年4月，Qalsody被FDA批准用于治疗超氧化物歧化酶1 (SOD1)突变所致的ALS。此外，目前全球还有多款在研ALS新疗法，详见下表。在研ALS疗法药物类型多样，涉及间充质干细胞疗法、基因疗法（ASO疗法和腺相关病毒（AAV）介导基因疗法）、Treg细胞疗法等，且有多款进入临床后期。全球部分在研ALS药物来源：公开资料01干细胞疗法干细胞疗法可以通过多种途径进行神经损伤修复，具有治疗ALS等多种中枢神经系统疾病潜力。过去十几年，ALS干细胞疗法的开发和临床转化取得了巨大的成就，据不完全统计，clinicaltrials官网登记的干细胞治疗ALS的临床研究数量超过40项。其中间充质干细胞作为能够保护运动神经元（MN）、分化为多种神经细胞类型、调节免疫细胞作用和减少中枢神经系统（CNS）炎症的细胞而脱颖而出。据悉，Corestem公司的间充质干细胞疗法NeuroNata-R已于2014在韩国获有条件批准用于治疗ALS，目前NeuroNata-R 联合利鲁唑治疗ALS的3期临床试验正在进行中。此外，Brainstorm公司的间充质干细胞疗法NurOwn®进展也较快。2020年11月，Brainstorm宣布NurOwn®在治疗ALS的3期临床试验中未能达到主要终点指标和关键次要终点，不过NurOwn®在病情较轻的患者组中产生了具有临床意义的作用。2022年11月，FDA在未对NurOwn®的BLA进行审查情况下就否决了其上市申请。02基因疗法自1993年发现第一个ALS致病基因，迄今为止，已有近30个基因被证实与ALS的发病相关，最常见的致病基因突变主要包括SOD1、TARDBP、FUS、OPTN、SQSTM1、DAO、DCTN1、VAPB、SIGMAR1、GRN、C9orf72等。近30年来，全球多款治疗ALS的基因疗法已进入临床试验阶段。在研ALS基因疗法包括反义寡核苷酸（ASO）疗法、腺相关病毒（AAV）介导的基因沉默/传递等多种创新疗法，其中首款治疗ALS的ASO药物Qalsody已于今年4月在美国获批。此外，ASO疗法中的ION363进展也较快，目前已进入3期临床。ION363是一种针对FUS RNA的反义药物，可减少FUS蛋白的产生。在FUS-ALS小鼠模型中，反义介导的突变FUS蛋白的还原可防止运动神经元丢失。通过针对FUS-ALS的根本原因，ION363具有减少或预防FUS-ALS患者疾病进展的潜力。2021年4月，ION363治疗FUS突变ALS患者的3期临床试验启动。WAVELife Sciences开发WVE-004是的一款针对C9orf72基因突变导致的ALS和额颞叶痴呆（FTD）的ASO药物，旨在选择性靶向含有与C9orf72基因相关的六核苷酸重复扩增（G4C2）的转录变体，从而保留C9orf72蛋白。C9orf72中的G4C2扩增是ALS和FTD散发性和遗传性形式的最常见遗传原因之一。目前， WVE-004正在进行一项针对42名与C9ORF72相关的ALS或FTD患者的1/2期安全性研究。AAV介导的ALS基因疗法进展相对较慢，其中Apic Bio开发APB-102由重组AAVrh10载体组成，该载体表达微核糖核酸（miRNA），旨在敲低SOD1的表达，目的是减缓或潜在逆转SOD1突变患者ALS的进展，目前已进入1/2期临床。Eikonoklastes Therapeutics的ET-101（SynCav1）是由加州大学圣地亚哥分校Brian Head博士实验室首创，用于过表达Caveolin-1的一种AAV9基因疗法，Caveolin-1可以组织和调节神经肌肉信号传导和功能所必需的突触受体。研究结果显示，增加Caveolin-1可以对神经细胞产生保护作用，使神经细胞可以补偿潜在疾病引起的神经退行性过程，并且使得细胞保持健康并提高其功能性。2022年12月，ET-101获得FDA孤儿药认定，用于治疗散发性和家族性ALS。03其他药物Treg细胞疗法也被开发用于治疗ALS，如ALS001。ALS001是一种自体的Treg细胞疗法，已被FDA授予的孤儿药资格。其1期临床结果表明，ALS001能够对神经起到保护作用，减缓ALS的进展。此外，Atibuclimab、Tegoprubart（AT-1501）等单抗也开发用于治疗ALS。其中Atibuclimab是一款靶向CD14的单克隆抗体，由小鼠可变区和人类IgG4 Fc区组成，可调节感染和损伤引发的致病性炎症反应。2021年1月，FDA授予Atibuclimab治疗ALS的孤儿药资格。Tegoprubart是一种靶向CD40L单抗，可阻断CD40L通路的激活，在ALS的临床前动物模型显示，CD40L通路可以改善肌肉功能、延缓疾病进展和提高存活率。在健康志愿者和患有ALS的成人开展的1a/1b期单次递增剂量试验显示，Tegoprubart在所有剂量下都表现出良好的耐受性，并显示出良好的安全性。而且，Tegoprubart在整个剂量范围内显示出线性剂量比例，半衰期长达26天。已公布的Tegoprubart治疗ALS的2a期临床试验结果显示：Tegoprubart表现出良好的耐受性，以及降低炎症相关生物标志物水平的作用。总结肌萎缩侧索硬化症(ALS)被WHO列为与艾滋病、癌症、白血病、类风湿等并列的五大绝症之一，然而目前该领域获批药物有限，ALS患者3年和5年死亡率分别为50%和80%。随着研究的深入，基因疗法、细胞疗法等药物治疗ALS的潜力已显现，期待未来有更好的ALS疗法获批上市，造福广大ALS患者。END👇关注药渡数据媒体矩阵

基因疗法信使RNA临床研究细胞疗法寡核苷酸

100 项与 SynCav-1 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
肌萎缩侧索硬化	临床前	美国	CavoGene LifeSciences	-
亨廷顿舞蹈病	药物发现	美国	Eikonoklastes Therapeutics, Inc.初创企业	2022-10-20
多发性硬化症	药物发现	美国	CavoGene LifeSciences	2020-09-08
帕金森病	药物发现	美国	CavoGene LifeSciences	2020-09-08
阿尔茨海默症	药物发现	美国	CavoGene LifeSciences	2018-10-23
创伤性脑损伤	药物发现	美国	CavoGene LifeSciences	2018-10-23
认知障碍	药物发现	美国	CavoGene LifeSciences	2018-10-23
脊髓损伤	药物发现	美国	CavoGene LifeSciences	2018-10-23