Transposon Engineered B Cell Therapy for Hunter Syndrome

转座子工程 B 细胞疗法治疗亨特综合症

• 批准号: 10087218
• 负责人: CHRISTIANE S HAMPE
• 金额: $ 46.68万
• 依托单位: IMMUSOFT CORPORATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087218
• 关键词: Address; Adoptive Transfer; Age; Allogenic; Animals; Applications Grants; Autologous; B cell therapy; B-Lymphocytes; Biological Assay; Blood; Bone Marrow Transplantation; Brain; Breathing; CCR6 gene; CD4 Positive T Lymphocytes; Cardiac; Cardiopulmonary; Cerebrospinal Fluid; Cessation of life; Clinical; Clinical Protocols; Clinical Trials; Data; Defect; Dermatan Sulfate; Development; Disease; Effectiveness; Engineering; Experimental Designs; Extraordinary Treatments; Gene Expression; Gene Transfer; Genes; Genetic; Genetic Engineering; Genomics; Glycosaminoglycans; Goals; Heart; Hematopoietic Stem Cell Transplantation; Heparitin Sulfate; Hepatosplenomegaly; Hereditary Disease; Human; Impairment; In Vitro; Infusion procedures; Laboratories; Leukocytes; Link; Lysosomal Storage Diseases; Mediating; Mental Retardation; Metabolic; Metabolic Diseases; Minnesota; Modeling; Modification; Mouse Strains; Mucopolysaccharidosis II; Mus; Nervous System Physiology; Neurocognitive; Neurologic; Neurologic Symptoms; Obstruction; Organ; Outcome; Pathway interactions; Patients; Penetration; Peripheral; Physiological; Plasma Cells; Prevention; Production; Proteins; Sleeping Beauty; Structure of choroid plexus; Symptoms; System; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Toxic effect; Treatment Protocols; Universities; blood cerebrospinal fluid barrier; bone; cell motility; cell type; chemokine receptor; enzyme replacement therapy; experience; functional restoration; genetically modified cells; iduronate-2-sulfatase; immunodeficient mouse model; in vivo; migration; mouse model; nervous system disorder; novel; novel strategies; novel therapeutics; phase 1 study; phase 2 study; pre-clinical research; preclinical study; protein function; receptor; research clinical testing; restoration; skeletal; skeletal abnormality; skeletal dysplasia; standard of care; therapeutic protein; treatment choice

PROJECT SUMMARY Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked recessive lysosomal disease caused by the absence of iduronate-2-sulfatase (IDS), resulting in systemic accumulation of glycosaminoglycan (GAG) storage materials, hepatosplenomegaly, skeletal dysplasias, cardiopulmonary obstruction, progressive neurologic impairment and death by age 12. MPS II is currently treated by enzyme replacement therapy, but these treatments are extraordinarily expensive and do not fully address the physiologic and neurologic manifestations of the disease. Here we propose an entirely novel approach to the treatment of MPS II. Immusoft Corp. is developing genetically engineered autologous human B cells for production of therapeutic proteins upon infusion into patients. Immusoft is using the Sleeping Beauty (SB) transposon system for integrative gene transfer and expression, as developed by Discovery Genomics, Inc. (DGI). In 2016 Immusoft acquired DGI, and here we propose to combine Immusoft’s novel B cell expression platform with the SB transposon technology for the purpose of expressing human IDS from B cells in vivo as an approach to achieve systemic and CNS-directed expression of IDS as a treatment for MPS II. This project is further strengthened by the extensive experience of Immusoft’s investigative team and colleagues at the University of Minnesota in the conduct of preclinical studies and clinical trials of new treatments for lysosomal diseases, including MPS II. For this Phase I study, the Specific Aims are; (i) Correction of IDS deficiency in a murine model of MPS II by adoptive transfer of human B cells genetically engineered to express human IDS using the Sleeping Beauty transposon system. IDS expressing human B cells will be infused into immunodeficient NSG MPS II mice recently established in the laboratory of the PI, evaluating recipient animals for adoptive transfer, expression and distribution of IDS activity, and correction of neurologic and physiologic disease. Treated animals will be evaluated for prevention of neurocognitive deficiency, skeletal defects and metabolic disease as a model for potential effectiveness in the treatment of human MPS II. (ii) Modification of B cells to promote transmigration of the blood-cerebrospinal fluid (CSF)-barrier. Human B cells will be genetically modified with SB transposons encoding CCR6 or CCR7, chemokine receptors that are known to mediate T-cell migration from the blood into the CSF. These transposed B cells will be tested for the ability to cross the blood-CSF-barrier using an in vitro transmigration assay, mimicking conditions at the blood-CSF barrier, and evidence for engineered B cell penetration of the CNS as a cellular vehicle for delivery of therapeutics for neurologic disease, including MPS II. Results from these studies will be directly applicable to the development of a clinical protocol for treatment of human MPS II by infusion of B cells genetically engineered to express human IDS using the SB transposon system.

项目摘要 粘多糖样变性II型（MPS II，亨特综合征）是一种X连锁隐性溶酶体疾病， 由于缺乏艾杜糖醛酸-2-硫酸酯酶（IDS），导致糖胺聚糖（GAG）全身蓄积 储存物质，肝脾肿大，骨骼发育不良，心肺阻塞，进行性 神经系统损伤和12岁死亡。MPS II目前通过酶替代疗法治疗，但 这些治疗非常昂贵，并且不能完全解决生理和神经问题， 疾病的表现。在这里，我们提出了一个全新的方法来治疗MPS II。 Immusoft公司正在开发基因工程自体人B细胞，用于生产治疗性 蛋白质输注到患者体内。Immusoft正在使用睡美人（SB）转座子系统 整合基因转移和表达，如Discovery Genomics，Inc.（DGI）。2016年Immusoft 获得DGI，在这里，我们建议将联合收割机Immusoft的新型B细胞表达平台与SB 转座子技术用于在体内从B细胞表达人IDS的目的， IDS的系统性和CNS定向表达作为MPS II的治疗。该项目得到了进一步加强， Immusoft的调查团队和明尼苏达大学的同事在 开展溶酶体疾病（包括MPS II）新疗法的临床前研究和临床试验。为 本I期研究的具体目的是：（i）通过以下方法纠正MPS II小鼠模型中的IDS缺陷： 使用Sleeping细胞过继转移经基因工程改造以表达人IDS的人B细胞 美容转座子系统。将表达IDS的人B细胞输注至免疫缺陷型NSG MPS II中 最近在PI实验室中建立的小鼠，评估受体动物的过继转移， IDS活性的表达和分布，以及神经和生理疾病的矫正。处理的动物 将作为模型评估神经认知缺陷、骨骼缺陷和代谢疾病的预防 治疗人类MPS II的潜在有效性。(ii)修饰B细胞以促进 血液-脑脊液（CSF）屏障的迁移。人类B细胞将被基因改造 与编码CCR 6或CCR 7的SB转座子，已知介导T细胞迁移的趋化因子受体 从血液进入脑脊液将检测这些转座B细胞穿过血液-CSF屏障的能力 使用体外迁移试验，模拟血液-CSF屏障的条件，以及 工程化的B细胞渗透中枢神经系统，作为递送神经系统疾病治疗药物的细胞载体， 包括MPS II。这些研究的结果将直接适用于临床开发 通过输注经基因工程改造以表达人MPS II的B细胞治疗人MPS II的方案 使用SB转座子系统的IDS。