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: 8245107
• 负责人: Katherine P. Ponder
• 金额: $ 32.75万
• 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/8245107
• 关键词: Address; Adult; Adverse effects; Age; Animal Model; Animals; Antibodies; Antibody Formation; Antigen-Presenting Cells; Biochemical; Biological Assay; Birth; Blood; Blood Cells; Bone Diseases; 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; Heparitin Sulfate; 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 diseases; 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; arthropathies; 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（由申请方提供）：粘多糖样沉积症I（MPS I）是一种由α-L-艾杜糖醛酸酶（IDUA）活性缺陷引起的溶酶体贮积病，导致糖胺聚糖类肝素和硫酸皮肤素蓄积。严重的形式，被称为赫尔勒综合征，导致骨骼和关节异常，肺部和心脏疾病，听力和视力缺陷，智力迟钝，如果不治疗，5岁左右死亡。造血干细胞移植可以减少一些表现，但有15%的死亡率，费用为13万美元，并需要一个兼容的供体。酶替代疗法也可以减轻一些症状，但成人每年的费用超过50万美元，需要每周输液，并且不是所有患者都可以使用。开发一种有效和安全的MPS I基因疗法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。在上一个资助期，我们证明了新生儿静脉注射具有完整长末端重复序列（LTR）表达犬IDUA的γ逆转录病毒载体（g-RV）在MPS I小鼠和犬中具有真正显著的效果，消除或减少了所有主要临床表现。这至少部分是由于肝细胞的有效转导，其将甘露糖6-磷酸（M6 P）修饰的IDUA分泌到血液中，其扩散到其他器官并通过M6 P受体摄取。还存在血细胞的一些转导和脑中的不确定细胞类型，这可能有助于治疗反应。虽然用这种方法在小鼠或狗中没有肿瘤发生，但用LTR完整载体插入诱变的风险是一个问题。另一个问题是，将该载体给予成年MPS I小鼠或新生MPS I猫导致破坏转换细胞的强效细胞毒性T淋巴细胞（CTL）应答。该更新申请的目的是：1）通过开发在3' LTR增强子中缺失的自失活g-RV来降低插入诱变的风险; 2）尝试通过避免在抗原呈递细胞中表达来预防免疫应答;以及3）分析有效性的持续时间并评价长寿大型动物模型（犬）中的毒性。如果成功，这项研究可能会加速开发一种简单有效的新生儿治疗方法，减少或预防MPS I的破坏性临床表现。 公共卫生相关性：该项目的目标是为粘多糖样沉积症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、关节和神经系统疾病，如果不治疗，严重的形式称为Hurler综合征，在5岁左右是致命的。该项目的目标是开发一种逆转录病毒载体，可以在出生后不久施用，并将导致长期纠正临床表现。这项研究还将测试基因治疗是否有任何副作用。这可能会导致对这种严重遗传疾病患者的治疗。