A Cross-Sectional, Observational Study of the Prevalence of Adenoviral-Specific Antibodies and Inflammatory Cytokines in Participants With Chronic Granulomatous Disease

This research study is designed to assess the prevalence of specific antibodies and inflammatory cytokines in adult and pediatric participants with CGD.

开始日期2024-10-01

申办/合作机构

Ensoma, Inc.初创企业

NCT05445128 / Terminated临床2期

A Phase 2, Open-Label Study to Evaluate the Efficacy and Safety of MGTA-145 in Combination With Plerixafor for the Mobilization of Hematopoietic Stem Cells in Patients With Sickle Cell Disease

This research study is designed to investigate a new potential medicine for mobilizing stem cells and apheresis collection in patients with Sickle Cell Disease. MGTA-145, the new potential medicine, will be given with plerixafor.

开始日期2022-06-24

申办/合作机构

Ensoma, Inc.初创企业

[+1]

NCT04762875 / Terminated临床2期

A Phase II Study Evaluating the Safety and Efficacy of MGTA-145 in Combination With Plerixafor for the Mobilization and Transplantation of HLA-Matched Donor Hematopoietic Stem Cells in Recipients With Hematological Malignancies

This research study tests a new medicine for mobilizing stem cells so they can be collected and used for allogeneic stem cell transplant for treatment of hematological malignancies. MGTA-145, the new medicine, will be given with plerixafor.

开始日期2021-06-16

申办/合作机构

Ensoma, Inc.初创企业

[+1]

100 项与 Ensoma, Inc. 相关的临床结果

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0 项与 Ensoma, Inc. 相关的专利（医药）

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项与 Ensoma, Inc. 相关的文献（医药）

2024-09-01·Molecular Therapy - Methods & Clinical Development

Auto-expansion of in vivo HDAd-transduced hematopoietic stem cells by constitutive expression of tHMGA2

Article

作者: Eluère, Raïssa ; Lieber, André ; Policastro, Robert A ; Georgakopoulou, Aphrodite ; Nizamis, Evangelos ; Wang, Hongjie ; Mok, Ka Wai ; Valdmanis, Paul N. ; Valdmanis, Paul N ; Policastro, Robert A.

We developed an in vivo hematopoietic stem cell (HSC) gene therapy approach that does not require cell transplantation. To achieve therapeutically relevant numbers of corrected cells, we constructed HSC-tropic HDAd5/35++ vectors expressing a 3' UTR truncated HMGA2 gene and a GFP reporter gene. A SB100x transposase vector mediated random integration of the tHMGA2/GFP transgene cassette. HSCs in mice were mobilized by subcutaneous injections of G-CSF and AMD3100/Plerixafor and intravenously injected with the integrating tHMGA2/GFP vector. This resulted in a slow but progressive, competitive expansion of GFP⁺ PBMCs, reaching about 50% by week 44 with further expansion in secondary recipients. Expansion occurred at the level of HSCs as well as at the levels of myeloid, lymphoid, and erythroid progenitors within the bone marrow and spleen. Importantly, based on genome-wide integration site analyses, expansion was polyclonal, without any signs of clonal dominance. Whole-exome sequencing did not show significant differences in the genomic instability indices between tHGMGA2/GFP mice and untreated control mice. Auto-expansion by tHMGA2 was validated in humanized mice. This is the first demonstration that simple injections of mobilization drugs and HDAd vectors can trigger auto-expansion of in vivo transduced HSCs resulting in transgene-marking rates that, theoretically, are curative for hemoglobinopathies.

2024-03-01·Molecular Therapy - Methods & Clinical Development

The comparability tales: A phase-appropriate roadmap for CGT drug product development

作者: Tomtishen, John ; Kassim, Sadik H ; Clément, Nathalie ; Spink, Katy ; Leblanc, Daniel

Cell and gene therapies (CGTs) have revolutionized patient outcomes and provided care options for previously untreatable conditions. The clinical and commercial progress of CGT therapies is hindered by chemistry, manufacturing, and control (CMC) challenges. This article summarizes recommendations from the 2023 Annual Meeting CMC sessions wherein speakers advocated for science-driven comparability strategies, proactive risk assessments, clearer regulatory guidance, and a shift from retrospective to prospective studies. Planning for manufacturing changes, statistical approaches, and consideration of multiple product versions also emerged as crucial elements to help sponsors navigate CMC hurdles for successful CGT clinical and commercial development.

2023-12-01·Nature Cell Biology

Leptin receptor+ cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor

Article

作者: Peyer, James G ; Zhang, Yixuan ; Tasdogan, Alpaslan ; Zhao, Zhiyu ; Ubellacker, Jessalyn M ; Crane, Genevieve M ; Embree, Claire ; Kara, Nergis ; Murphy, Malea M ; Shen, Bo ; Fang, Shentong ; Guo, Jiaming ; Morrison, Sean J ; Yang, Min ; Gao, Xiang ; Ni, Yuehan

AbstractThe bone marrow contains peripheral nerves that promote haematopoietic regeneration after irradiation or chemotherapy (myeloablation), but little is known about how this is regulated. Here we found that nerve growth factor (NGF) produced by leptin receptor-expressing (LepR+) stromal cells is required to maintain nerve fibres in adult bone marrow. In nerveless bone marrow, steady-state haematopoiesis was normal but haematopoietic and vascular regeneration were impaired after myeloablation. LepR+ cells, and the adipocytes they gave rise to, increased NGF production after myeloablation, promoting nerve sprouting in the bone marrow and haematopoietic and vascular regeneration. Nerves promoted regeneration by activating β2 and β3 adrenergic receptor signalling in LepR+ cells, and potentially in adipocytes, increasing their production of multiple haematopoietic and vascular regeneration growth factors. Peripheral nerves and LepR+ cells thus promote bone marrow regeneration through a reciprocal relationship in which LepR+ cells sustain nerves by synthesizing NGF and nerves increase regeneration by promoting the production of growth factors by LepR+ cells.

项与 Ensoma, Inc. 相关的新闻（医药）

2024-09-30

·EndPoints

Ensoma shutters Copenhagen site from its Twelve Bio acquisition

Genomic medicines startup Ensoma is shuttering its Copenhagen site and also eliminating “a very small number” of roles at its Boston office, a spokesperson confirmed to Endpoints News . Multiple employees from the Copenhagen lab have recently posted about the closure on LinkedIn. Ensoma, which just turned five years old, assumed control of the location through its acquisition last year of Twelve Bio. The Twelve Bio deal was announced at the time of Ensoma’s $85 million financing in January 2023. Founded in 2019 and based on research at the Novo Nordisk Foundation Center for Protein Research, Twelve Bio was working on engineering CRISPR-Cas12a into “wholly novel sequences with unique properties useful for a range of DNA editing strategies.” Boston-based Ensoma is working on in vivo gene editing of blood and immune cells to make off-the-shelf therapies that could potentially be safer than ex vivo cell therapies. “Since acquiring Twelve Bio, we’ve made significant progress in advancing next-generation base editing technology. With the successful completion of essential work by our Copenhagen team, we have identified opportunities to streamline operations and extend our operational runway,” the spokesperson said in an emailed statement. That includes work in CGD, solid tumors and sickle cell disease. The spokesperson declined to disclose how many staffers are being laid off. Ensoma had about 90 employees as of May, CEO Jim Burns told Endpoints at the time. He said the company would add a chief business officer, look for more partnerships after Takeda backed out of a pact, and look at more financing around early 2025. “The idea of in vivo gene editing of immune cells is a great idea. It’s based on really good science, too, so it could work,” Burns told Endpoints in May. “But that’s not sufficient. You have to be able to execute” to turn it into a therapeutic product, he said. Ensoma is one of multiple genetic medicines startups to downsize or prioritize its pipeline in recent quarters, alongside Prime Medicine , Arbor Biotechnologies and others. Burns joined Ensoma after his last biotech, gene therapy company Locanabio, shuttered last winter. The biotech plans to file an IND in the first half of next year for chronic granulomatous disease, according to its website.

并购基因疗法

2024-09-06

·同写意

体内制造CAR-T细胞疗法的前沿进展和挑战

体外制造T细胞策略在制备过程和成本上面临极大挑战，限制了其可及性。为了解决这些问题，近年来研究人员积极探索和开发体内制造CAR-T细胞疗法，已有疗法进入临床阶段。 2024年8月，“柳叶刀发现科学（Lancet Discovery Science）”系列杂志之《eBioMedicine》杂志发布了一篇题为“Advancements and challenges in developing in vivo CAR T cell therapies for cancer treatment”的文章。该文章总结了癌症治疗中体内制造CAR-T细胞疗法的最新进展与挑战。 1 体外CAR-T疗法和体内CAR-T疗法简介除了要克服治疗中的主要困难（如CRS和免疫逃逸）外，体外CAR-T疗法在产业化发展和制备工艺方面存在重大挑战。首先，体外制造CAR-T疗法涉及T细胞分离、改造和体外扩增，然后再重新注入人体（图2），其过程耗时且复杂，持续数周。这一较长的周期不利于因癌症快速进展而需要紧急治疗的患者。此外，这种制造过程还带来了物流和安全挑战，需要将患者的细胞运送至专业的制造设施。它在技术上要求高且成本昂贵。图2 | 体外CAR-T疗法过程示意图体内制造CAR-T疗法利用包含基因编辑工具的递送载体，直接在患者体内将T细胞改造成CAR-T细胞（图3）。与体外CAR-T疗法相比，体内CAR-T疗法有望降低生产成本，缩短周转时间，并为患者提供更大的便利。图3 | 体内CAR-T疗法过程示意图多种基因编辑系统被用来转导原代T细胞，使之稳定表达CAR。这些包括转座子、锌指核酸酶（ZFNs）、转录激活因子效应核酸酶（TALENs）和CRISPR系统。在这四种编辑工具中，转座子、ZFN和CRISPR系统同时适用于体内和体外制造CAR-T细胞。 2 体内制造CAR-T细胞的递送系统及靶向T细胞递送CAR构建物的进展体内递送CAR需要满足一定的标准，包括精确的T细胞靶向、高效的基因编辑和低毒性。目前，病毒载体和纳米载体被广泛探索用于体内递送CAR构建物（图4）。图4 | 体内制造CAR-T细胞的递送载体用于CAR-T细胞疗法的病毒载体，通常通过瞬时转染源质粒到HEK-293T或生产病毒的细胞系中，将CAR基因克隆到病毒载体来制备。对于体内制造CAR-T细胞，这些病毒载体可以进一步工程化，通过结合T细胞靶向配体来特异性靶向T细胞。这些配体可以通过基因融合到病毒包膜蛋白上，或通过化学偶联附着在病毒载体上。精确靶向T细胞是影响体内CAR-T疗法效果和安全性的关键因素。使用病毒载体和纳米载体开发靶向T细胞递送CAR策略和体内CAR-T疗法的实验结果列在表1中。表1 | 体内CAR-T治疗癌症的临床前研究 3 病毒载体用于体内制造CAR-T细胞的主要病毒类型包括慢病毒、逆转录病毒和腺相关病毒（AAV）。 Pfeiffer等人首次通过注射靶向CD8+ T细胞的慢病毒载体（LV）来递送CD19-CAR，直接在体内制造CAR-T细胞。Michels等人（VivoVec）开发了抗CD3的scFv修饰的LV，用于在体内CD3+ T细胞中构建抗CD19 CAR。 Agarwalla等人开发了一种可植入的多功能支架，该支架能够同时装载患者来源的T细胞和编码CD19的逆转录病毒颗粒，用于体内制造CAR-T细胞，将整个过程缩短至一天。这种支架通过皮下植入后，αCD3和αCD28介导细胞激活，白介素介导增殖，这促进了T细胞的体内激活和扩增。它能够在5天内持续释放功能完全的CAR-T细胞，并在控制肿瘤生长方面达到与体外CAR-T疗法相当的效果，同时在肿瘤清除后细胞扩增更好和更持久。有研究显示，用T细胞受体-CD3复合物（CD3-LVs）修饰的LV可以特异性识别并转染循环T细胞以产生CAR基因，这成功地将CD19特异性CAR基因递送到人源化NSG小鼠的T细胞中，进而消除CD19+细胞。另一项研究中，通过用抗CD3抗体改造偶氮（azide）基团修饰的LV，研究人员建立了一个工程化双特异性LV平台。这些LV在体外和体内都实现了靶向T细胞递送CD19-CAR基因。 AAV也被应用于体内制造CAR-T细胞。在人T细胞白血病的小鼠模型中，研究人员利用AAV-DJ，即2型、8型和9型AAV的嵌合体，将编码CD4 CAR基因的质粒递送到T细胞。然而，关键技术挑战是AAV缺乏用于定向递送到目标部位的膜包裹（membrane envelope）。因此，AAV载体的体内基因递送需要精确选择AAV血清型，进行组织特异性递送或用靶向T细胞的构建物修饰AAV衣壳蛋白。例如，经设计的锚蛋白重复蛋白（designed ankyrin repeat proteins，DARPins）可以插入到AAV2衣壳蛋白中，以特异性靶向小鼠CD8 T细胞，使小鼠脾细胞中CAR基因递送增加了20倍。该团队进一步工程化双特异性DARPins-AAV2以双重靶向CD4和CD32a，促进了T细胞靶向和体内CAR基因产生。尽管在临床前阶段取得进展，病毒载体因其可能触发免疫反应和引起组织炎症，其安全问题不容忽视。 4 纳米载体纳米载体也显示出在体内向T细胞递送遗传物质（如mRNA、质粒和蛋白质）以引入CAR构建物的潜力。与病毒载体相比，纳米载体的脱靶毒性和免疫原性极小，并且可以大规模生产。此外，纳米载体可以通过与不同的靶向生物材料结合来定制设计，以提高靶向能力。此外，它们可以通过化学偶联和冻干处理以延长稳定性。目前，聚合物（polymers）、脂质（lipids）和外泌体（exosomes）是最常用的体内制造CAR T细胞的纳米载体。阳离子聚合物纳米粒子可以通过静电凝聚（electrostatic condensation）与负电荷核酸形成复合物。复合物表面带正电荷，可通过静电结合到带负电的细胞膜上，以增强细胞摄取。由于这些复合物能够避免酶降解，并通过它们的质子海绵（proton sponge）效应逃避内体（endosomes），因此他们更稳定。 Smith等人开发了用于体内CAR T疗法的聚合物纳米载体，使用靶向CD3的生物可降解、聚（β-氨基酯）基纳米粒子将特异性CAR基因递送到白血病小鼠模型中的T细胞，可使白血病消退且副作用很小。在尾静脉注射后4小时，这些靶向T细胞的聚合物纳米粒子成功将CAR基因转染到循环T细胞中。这种治疗策略在免疫功能正常的白血病小鼠以及携带实体瘤的免疫缺陷小鼠中都有效。该系统后来也适用于CAR-mRNA和T细胞受体-mRNA递送，在白血病、前列腺癌和乙型肝炎病毒诱导的肝细胞癌的小鼠模型中可有效重新编程T细胞。然而，这些研究都缺乏对CAR转基因递送的量化评估。此外，阳离子聚合物在宿主中的生物降解性和不稳定性可能会降低CAR生产能力，并可能抵消体内CAR-T疗法的治疗效果。同时，阳离子聚合物的高毒性需要进一步工程化，包括脂质共复合，以减轻毒性并增强功能。脂质纳米粒子和外泌体也在促进体内T细胞重编程方面显示出潜力。 Zhou等人开发了载有白细胞介素6短发夹RNA（IL-6 shRNA）和CD19-CAR组合基因（AntiCD3-LNP/CAR19 + shIL6）质粒的靶向CD3脂质纳米载体。这些纳米载体选择性地靶向循环T细胞，使白血病小鼠中CAR表达增加和CAR T细胞的抗肿瘤效果延长，持续至给药后41天，与体外T细胞疗法相当。此外，IL6-shRNA的联合降低了CRS的风险。 Fan等人通过用抗CD3和抗表皮生长因子受体(EGFR)抗体修饰的、肿瘤抗原刺激的、树突状细胞衍生的外泌体（tDC-Exo），开发了一个CAR-T平台，允许同时靶向内源性T细胞和癌细胞。然而，外泌体尺寸小，难以有效地包装大型基因编辑工具，如CRISPR/Cas9 RNP。为了解决这一挑战，科学家们探索了各种策略，包括外泌体工程和混合递送系统。 5 体内CAR-T疗法产业化发展基于病毒载体的体内CAR-T疗法已有产业转化。例如，与前述Umoja Biopharma推出的VivoVec™同期，EXUMA Biotech已开发了一种编码CD19 CAR的LV，用于在人源化NSG-SGM3小鼠模型中靶向和激活CD3+ T细胞。他们的临床前数据显示，体内编辑CD3+ T细胞可产生功能性CAR T细胞，并清除B细胞。此外，该公司开发了针对HER2阳性复发或难治性IV期转移性实体瘤的新治疗策略，目前正在进行I期临床研究。基于纳米粒子的体内CAR-T疗法的产业转化也有进展。例如，Ensoma开发了一种病毒样颗粒Engenious™平台，可以递送高达35千碱基对的包装DNA基因材料，是AAV载体上限的七倍以上。Capstan Therapeutics利用mRNA-脂质纳米粒子平台，在心脏病小鼠模型中成功制造了体内CD5特异性CAR T细胞。该公司使用靶向CD5离子化脂质纳米粒子（CD5/LNP）包裹针对成纤维细胞激活蛋白的CAR mRNA分子。在LNP注射后48小时，一个新的CAR-T细胞亚群出现了，占总T细胞群的20%。 6 体内CAR-T疗法开发中的挑战如前所述，体内CAR-T疗法的一个主要问题是如何有效地将CAR转基因递送到体内的目标T细胞中。病毒载体可以促进细胞摄取和核穿透，然而，直接向患者注入携带CAR构建物的病毒载体，其靶向能力有限。此外，这种方法还带来了脱靶效应的风险，其他细胞类型可能被转染。工程化病毒载体有望增强其靶向递送至T细胞的能力。纳米载体平台相比病毒载体，相关的风险和生产成本较低，似乎更适合于体内靶向T细胞，但还需要额外的研究来提高这些纳米粒子在生物环境中的稳定性和生物相容性，以防止它们在到达并靶向T细胞之前，在体内被降解和产生潜在的不良反应。与纳米载体相关的另一个主要问题是它们有限的转染效率。在临床环境中使用的脂质纳米粒子从内/溶酶体（endo/lysosomal）室逃逸进入细胞质之前，可能导致遗传物质（如mRNA）在溶酶体中被酶降解。质粒DNA的一个额外障碍是必须将其运输到细胞核中进行转录，然后在细胞质中翻译成蛋白质。为了解决这个问题，研究人员已开发了多种策略，包括使用pH反应性纳米载体和结合触发逃逸机制的成分，如孔形成蛋白或肽。与体外CAR-T疗法类似，体内CAR-T疗法对于实体瘤的治疗比血液恶性肿瘤更具挑战性。在临床前研究中使用的动物模型的临床相关性对于成功的治疗开发也至关重要。非人灵长类动物模型将对评估体内CAR T细胞产品的安全性和药代动力学特性至关重要。 7 体内CAR-T疗法的监管考量与体外CAR-T疗法一样，体内CAR-T疗法若要在临床上复制临床前的成功，在临床环境中的安全性和有效性非常重要。监管机构如美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）要求病毒和纳米载体在批准之前遵守严格的质量、安全和有效性标准。譬如，由于脂质纳米载体在健康组织中的积累可能导致细胞毒性和/或遗传毒性，毒理学评估对于确保脂质纳米载体符合法规至关重要。在临床用于递送CAR基因的病毒载体也需要仔细测试其纯度、安全性、稳定性和功能性。某些用于递送CAR的病毒载体有致癌插入性突变风险，或在修饰的T细胞中触发不必要的炎症反应，极少情况下会偶发癌变。另一个关于体内CAR-T疗法的监管问题是基因编辑工具的安全性，如CRISPR/Cas9系统。譬如，它可能导致在目标T细胞内非目标位点引入可变长度插入/缺失（indel），从而可能导致功能基因中断和表观遗传修饰，使疗效降低，甚至在宿主中导致过度的细胞因子释放或不良免疫反应等危险后果。为了最小化CRISPR/Cas9编辑工具在体内外修饰T细胞期间的脱靶效应，可以考虑使用高保真Cas9变体。 — 结论 — 作为一种可行的现货型替代，体内CAR-T疗法有潜力提高安全性和有效性，减少治疗等待时间，免除清淋化疗，为患者提供更大的便利。参考文献： Bui TA, Mei H, Sang R, et al. Advancements and challenges in developing in vivo CAR T cell therapies for cancer treatment. EBioMedicine. 2024 Aug;106:105266. doi: 10.1016/j.ebiom.2024.105266. Epub 2024 Aug 1. PMID: 39094262. 同写意媒体矩阵，欢迎关注↓↓↓

细胞疗法免疫疗法基因疗法

2024-08-06

·PRNewswire

BioInnovation Institute enters into a collaboration with MIT and UNC to support new Bio Studio project

COPENHAGEN, Denmark, Aug. 6, 2024 /PRNewswire/ -- BioInnovation Institute (BII), an international non-profit foundation, incubating and accelerating world-class life science research, today announces it has entered into a collaboration with Massachusetts Institute of Technology (MIT) and the University of North Carolina (UNC) to support a research project through its company creation program, Bio Studio. Under the terms of the collaboration agreement, BII will contribute to the funding of the Project by means of a grant with a total annual market value of up to DKK 7,860,000, for a project period of up to three years. Alongside the grant, BII will support the project with business development expertise, intellectual property support, access to investor network, and both wet lab and office infrastructure. The Bio Studio project, named Pivot, will focus on how mucus can combat antibiotic resistance. The project aims to leverage the mucus barrier, an essential component of the innate immune system, to address the unmet medical needs of chronic lung diseases. The project will be led by Principal Investigators, Professor Katharina Ribbeck and Associate Professor Matthew Wolfgang. Katharina Ribbeck, Professor of Biological engineering at MIT, leads The Ribbeck Lab which has become a world-leader in elucidating the role of mucus and the basic mechanisms of the mucus barrier. Matthew Wolfgang, Associate Professor at the Department of Microbiology and Immunology and the Marsico Lung Institute at UNC, leads the team at The Wolfgang Lab and focuses on the pathogenesis of chronic respiratory infection in muco-obstructive airway diseases. Trine Bartholdy, Chief Innovation Officer at BioInnovation Institute said: "We are excited to enter into a collaboration with world-leading research institutes, MIT and UNC. The Pivot project is a fantastic addition to our Bio Studio portfolio as antibiotic resistance remains a key concern for society. The combination of expertise from both Prof. Ribbeck and Associate Prof. Wolfgang is a truly unique asset for this project and we look forward to supporting the team in developing innovative solutions to address antibiotic resistance." Professor Katharina Ribbeck, Principal Investigator at Massachusetts Institute of Technology added: "The critical role of the mucus barrier has been overshadowed by the historical emphasis on antibiotics. However, with antibiotic resistance presenting a growing global threat, leveraging the power of this natural defense system offers a new frontier in therapeutic development. By harnessing the potential of the mucus barrier, a cornerstone of our innate immune system, we can achieve significant benefits for patients and society as a whole. BII's Bio Studio program provides the perfect platform to explore the commercial potential of this innovative science and pave the way for company creation." Professor Matthew Wolfgang, Principal Investigator at University of North Carolina said: "As the prevalence of lung disease and chronic lung infection continue to increase world-wide, there is a dire need for new more effective therapies to treat these highly recalcitrant infections. I am thrilled to be part of this innovative team and look forward to advancing Pivot to the next level with the support of the Bio Studio program." Read more about the Bio Studio program here. About the BioInnovation Institute Foundation: At BioInnovation Institute (BII), we accelerate world-class life science start-up innovation for the benefit of people and society. As a non-profit institute, BII operates the company creation programs, Bio Studio, Venture Lab and Venture House, to support life science start-ups with knowledge, network, infrastructure and funding of up to 3M EUR per projects and 1,8 M EUR per start-up. With our expertise, network, funding, and infrastructure, we empower startups to succeed and believe in the transformative power of life science innovation. Read more on Since its inception in 2018, BII has supported 100 start-ups and projects with EUR 97 million alongside the venture capital, industry and business expertise it provides to help them accelerate to the next level. In total, BII's start-ups have raised over EUR 428 million in external funding from both local and international investors. Recent company successes include, Adcendo, Stipe Therapeutics, Twelve Bio, Octarine Bio, and Cirqle Biomedical. SOURCE BioInnovation Institute

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