RETROVIRAL VECTOR-MEDIATED LIVER GENE THERAPY FOR MPS I

逆转录病毒载体介导的 MPS I 肝基因治疗

• 批准号: 7752811
• 负责人: Katherine P. Ponder
• 金额: $ 36.51万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7752811
• 关键词: Address; Adult; Adverse effects; Age; Animal Model; Animals; Antibodies; Antibody Formation; Antigen-Presenting Cells; Biochemical; Biological Assay; Birth; Blood; Blood Cells; Brain; Canis familiaris; Caring; Cells; Cessation of life; Chromosomes; Clinical; Clinical Data; Complementary DNA; Cytotoxic T-Lymphocytes; Dermatan Sulfate; Development; Diffuse; Disease; Echocardiography; Enhancers; Enzymes; Evaluation; Family; Felis catus; Funding; Genetic Enhancer Element; Glycosaminoglycans; Goals; Hearing; Heart; Heart Diseases; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hepatocyte; Hereditary Disease; Human; IGF Type 2 Receptor; Immune response; Immune system; Immunosuppression; Infusion procedures; Injection of therapeutic agent; Insertional Mutagenesis; Joints; L-Iduronidase; Lentivirus Vector; Life; Liver; Long Terminal Repeats; Longevity; Lung; Lysosomal Storage Diseases; Malignant Neoplasms; Mediating; Mental Retardation; Modeling; Mucopolysaccharidosis I; Mucopolysaccharidosis I H; Mus; Neonatal; Newborn Infant; Oncogenes; Oncogenic; Ophthalmic examination and evaluation; Organ; Patients; Proteins; RNA; Retroviral Vector; Risk; Serum; Symptoms; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Transducers; Treatment Efficacy; Visual; bone; cell type; clinical effect; cost; effective therapy; enzyme replacement therapy; gamma-A; gene therapy; in vivo; intravenous injection; leukemia; mannose 6 phosphate; mortality; nervous system disorder; null mutation; pre-clinical; prevent; promoter; public health relevance; research study; response; skeletal; transmission process; tumor; vector

DESCRIPTION (provided by applicant): Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease caused by deficient a-L-iduronidase (IDUA) activity, which results in the accumulation of the glycosaminoglycans heparan and dermatan sulfate. The severe form, known as Hurler syndrome, causes bone and joint abnormalities, pulmonary and cardiac disease, hearing and visual deficiencies, mental retardation, and death around age 5 if untreated. Hematopoietic stem cell transplantation can reduce some manifestations, but has a 15% mortality rate, costs $130,000, and requires a compatible donor. Enzyme replacement therapy can also reduce some symptoms, but costs over $500,000 per year for an adult, requires a weekly infusion, and is not available to all patients. The development of an effective and safe gene therapy for MPS I could have a dramatic positive impact on the lives of patients and the families that care for them. In the previous funding period, we demonstrated that neonatal intravenous injection of a gamma retroviral vector (g-RV) with an intact long-terminal repeat (LTR) expressing canine IDUA had a truly remarkable effect in both mice and dogs with MPS I, with elimination or reduction in all major clinical manifestations. This was due at least in part to efficient transduction of liver cells, which secreted mannose 6-phosphate (M6P)-modified IDUA into blood, which diffused to other organs and was taken up via the M6P receptor. There was also some transduction of blood cells and an undefined cell type in brain, which may have contributed to the therapeutic response. Although no tumors developed in mice or dogs with this approach, the risk of insertional mutagenesis with an LTR-intact vector is a concern. Another problem is that administration of this vector to adult MPS I mice or newborn MPS I cats resulted in a potent cytotoxic T lymphocyte (CTL) response that destroyed transducer cells. The aims of this renewal application are to: 1) reduce the risk of insertional mutagenesis by developing a self-inactivating g-RV with a deletion in the enhancer of the 3' LTR; 2) attempt to prevent an immune response by avoiding expression in antigen-presenting cells; and 3) analyze the duration of efficacy and evaluate for toxicity in a long-lived large animal model (dog). If successful, this study may hasten the development of a simple and effective treatment for newborn patients that will reduce or prevent the devastating clinical manifestations of MPS I. Public Health Relevance: The goal of this project is to develop a simple and effective treatment for patients with mucopolysaccharidosis I (MPS I). MPS I results in heart, lung, bone, joint, and neurological disease, and in the severe form known as Hurler syndrome is fatal around age 5 if untreated. The goal of this project is to develop a retroviral vector that can be administered shortly after birth, and will result in long-standing correction of the clinical manifestations. This study will also test to see if there are any adverse effects of gene therapy. This may result in a treatment for patients with this severe genetic disease.

描述（由申请人提供）：粘多糖I（MPS I）是由不足A-L-二维罗苷酶（IDUA）活性引起的溶酶体储存疾病，这导致糖胺聚糖乙酰肝素和硫酸甲基糖的甘氨酸聚糖堆积。严重的形式被称为h综合征，会导致骨骼和关节异常，肺部和心脏疾病，听力和视觉缺陷，智力低下以及5岁左右的死亡，如果未经治疗。造血干细胞移植可以减少一些表现，但死亡率为15％，成本为130,000美元，需要兼容的供体。酶替代疗法也可以减轻某些症状，但成人每年的成本超过500,000美元，需要每周输注，并且所有患者并非可用。为MPS开发有效且安全的基因疗法，我可能会对患者和照顾他们的家庭的生活产生巨大的积极影响。在上一个资金期间，我们证明了新生儿静脉注射γ逆转录病毒载体（G-RV）具有完整的长末端重复重复（LTR）表达犬Idua的犬Idua在所有主要临床表现中消除或减少MPS I的小鼠和狗都具有显着作用。这至少部分是由于肝细胞有效地转导的，后者分泌的6-磷酸甘露糖（M6P）改性为血液，该血液扩散到其他器官，并通过M6P受体吸收。血细胞也有一些转导和大脑中未定义的细胞类型，这可能有助于治疗反应。尽管在使用这种方法的小鼠或狗中没有肿瘤，但具有LTR-Intact载体插入诱变的风险是一个问题。另一个问题是，将该载体施用到成年MPS I小鼠或新生MPS I CAT导致有效的细胞毒性T淋巴细胞（CTL）反应破坏了传感器细胞。该更新应用的目的是：1）通过在3'LTR的增强子中开发自动化的G-RV来降低插入诱变的风险； 2）试图通过避免在抗原呈递细胞中表达表达来防止免疫反应； 3）分析疗效的持续时间并评估长期寿命的大动物模型（DOG）中的毒性。如果成功的话，这项研究可能会加快为新生儿的简单有效治疗的开发，以减少或防止MPS I的毁灭性临床表现。 公共卫生相关性：该项目的目的是为粘多糖尿病I（MPS I）患者开发一种简单有效的治疗方法。 MPS I导致心脏，肺，骨骼，关节和神经系统疾病，并以严重的形式称为Hurler综合征，如果未治疗，则为5岁左右致命。该项目的目的是开发可以在出生后不久进行管理的逆转录病毒载体，并将长期纠正临床表现。这项研究还将测试基因治疗是否有任何不良影响。这可能会导致对这种严重遗传疾病的患者进行治疗。