Retroviral Vector-Mediated Liver Gene Therapy for MPS I

逆转录病毒载体介导的 MPS I 肝脏基因治疗

• 批准号: 7446367
• 负责人: Katherine P. Ponder
• 金额: $ 8.1万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7446367
• 关键词: Adolescent; Adult; Age; Animal Model; Animals; Antigen-Presenting Cells; Aorta; Aortic Diseases; Biology; Birth; Brain; Brain Pathology; Breeding; Canis familiaris; Cathepsins; Cell Line; Cell Transplantation; Cessation of life; Clinical; Clinical Trials; Complementary DNA; Cytokine Gene; Cytotoxic T-Lymphocytes; DNA; Dermatan Sulfate; Developed Countries; Developing Countries; Diffusion; Dilatation - action; Disease; Dose; Effector Cell; Elastases; Elastin; Engineering; Enzymes; Etiology; Felis catus; Functional disorder; Funding; Glycosaminoglycans; Goals; Hearing; Heart Diseases; Hematopoietic Stem Cell Transplantation; Hepatocyte; Human; IGF Type 2 Receptor; Immune; Immune Response Genes; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; In Vitro; Injection of therapeutic agent; Joints; Knowledge; L-Iduronidase; Liver; Lung; Lysosomal Storage Diseases; Macaca mulatta; Mediating; Mental Retardation; Modification; Mucopolysaccharidosis I; Mucopolysaccharidosis I H; Mus; Neonatal; Newborn Infant; Organ; Pancreatic Elastase; Pathogenesis; Pathological Dilatation; Patients; Primates; Process; Proteins; RNA; Rate; Refractory; Retroviral Vector; Serum; Spleen; Symptoms; Testing; Therapeutic immunosuppression; Time; Transcriptional Activation; Translating; Up-Regulation; Visual; base; bone; cellular transduction; clinical effect; cognitive function; cost; dosage; enzyme replacement therapy; gene therapy; improved; interest; lymph nodes; mannose 6 phosphate; matrix metalloproteinase 12; mortality; nervous system disorder; nonhuman primate; preclinical study; prevent; research study; response; tumor; uptake; vector

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 results in bone and joint abnormalities, pulmonary and cardiac disease, hearing and visual deficiencies, mental retardation, and death by age 10 if untreated. Hematopoietic stem cell transplantation can reduce certain manifestations, but has a 20% mortality rate. Enzyme replacement therapy can also reduce some symptoms, but is not supported for Hurler syndrome in some developed countries due to the cost and inability to prevent neurological disease at the doses used. In the previous funding period, we demonstrated that neonatal IV injection of a retroviral vector (RV) expressing canine IDUA resulted in efficient transduction of liver cells and high serum IDUA activity in both mice and dogs with MPS I. This resulted in correction of disease in organs throughout the body including the brain, which was likely due to diffusion of IDUA into organs and uptake of mannose 6-phosphate (M6P)-modified enzyme via the M6P receptor. We have also transduced hepatocytes in adult MPS I mice and corrected many manifestations of disease. However, adults required immunosuppression to prevent cytotoxic T lymphocytes (CTLs) from destroying transduced cells, disease in aorta was not prevented, and it was not clear if pathological improvements in the brain resulted in a smarter mouse. Aim I of this renewal application will be to determine if an immune response can be prevented in adults by engineering the vector to avoid expression in antigen presenting cells, and will further evaluate the effect of disease in the aorta and brain. Although neonatal gene therapy was effective and did not evoke an immune response in mice or dogs, newborn cats developed a potent CTL response to canine IDUA after neonatal gene therapy. In addition, humans have a more mature immune system at birth than mice. Aim II will be to compare the expression of immune response genes in spleen and lymph nodes from newborn, juvenile, and adult cats, dogs, and nonhuman primates. Aim III will develop an RV expressing the human IDUA protein to be used for a clinical trial for neonatal patients with Hurler syndrome who are without alternative treatment options. Finally, aim IV will evaluate the pathogenesis of aortic dilatation, which appears to be due to up-regulation of enzymes that degrade elastin. These studies may translate into improved treatment for MPS I patients.

I 型粘多糖贮积症 (MPS I) 是一种由 α-L-艾杜糖醛酸酶缺陷引起的溶酶体贮积病 (IDUA) 活性，导致糖胺聚糖乙酰肝素和硫酸皮肤素的积累。 被称为 Hurler 综合征的严重形式会导致骨和关节、肺和心脏异常 疾病、听力和视力缺陷、精神发育迟滞，如果不及时治疗，可能会在 10 岁时死亡。 造血干细胞移植可以减轻某些表现，但死亡率为20%。 酶替代疗法也可以减轻一些症状，但不支持用于 Hurler 综合征 一些发达国家由于成本高且无法以所使用的剂量预防神经系统疾病。在 在之前的资助期间，我们证明了新生儿静脉注射表达逆转录病毒载体（RV） 犬 IDUA 导致小鼠和小鼠肝细胞的有效转导和高血清 IDUA 活性 患有 MPS I 的狗。这导致了包括大脑在内的整个身体器官的疾病得到纠正， 这可能是由于 IDUA 扩散到器官中并摄取了 6-磷酸甘露糖 (M6P) 修饰的 通过 M6P 受体的酶。我们还在成年 MPS I 小鼠中转导了肝细胞并纠正了 疾病的多种表现。然而，成年人需要免疫抑制来预防细胞毒性 T 淋巴细胞（CTL）破坏转导细胞，主动脉疾病没有被预防，也没有被预防。 明确大脑的病理改善是否会导致老鼠变得更聪明。本次续签申请的目的一 将确定是否可以通过设计载体来避免成人的免疫反应 在抗原呈递细胞中表达，并将进一步评估疾病对主动脉和大脑的影响。 尽管新生儿基因疗法是有效的，并且没有在小鼠或狗中引起免疫反应， 新生儿基因治疗后，新生猫对犬 IDUA 产生了有效的 CTL 反应。此外， 人类在出生时就比小鼠拥有更成熟的免疫系统。目标 II 是比较 新生儿、幼年和成年猫、狗和非人类的脾脏和淋巴结中的免疫反应基因 灵长类动物。 Aim III 将开发表达人类 IDUA 蛋白的 RV，用于临床试验 适用于没有其他治疗选择的 Hurler 综合征新生儿患者。最后，目标 IV 将 评估主动脉扩张的发病机制，这似乎是由于酶的上调所致 降解弹性蛋白。这些研究可能会改善 MPS I 患者的治疗。