Pulmonary endothelium targeted adenoviral gene therapy for the correction of mucopolysaccharidosis type I

肺内皮靶向腺病毒基因治疗纠正 I 型粘多糖贮积症

• 批准号: 10678053
• 负责人: Sarah Hurt
• 金额: $ 3.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678053
• 关键词: Address; Adenovirus Vector; Adenoviruses; Affect; Alternative Therapies; Antibodies; Binding; Biochemical; Biological Assay; Blood Circulation; CRISPR/Cas technology; Capsid; Cells; Cellular Morphology; Cessation of life; Clinical; Clinical Trials; Consumption; Developmental Delay Disorders; Disease; Dose; Elements; Employment; Endothelial Cells; Endothelium; Enzymes; Face; Fiber; Future; Gene Transduction Agent; Genes; Genetic Diseases; Genome; Glycosaminoglycans; Goals; Heart Diseases; Hepatotoxicity; Histologic; Immune response; Immune system; Individual; Infection; Inherited; L-Iduronidase; Life Expectancy; Liver; Loss of Heterozygosity; Lung; Lysosomes; Mendelian disorder; Methods; Modeling; Modification; Molecular; Mucopolysaccharidosis I; Mucopolysaccharidosis I S; Mutation; Myelogenous; Newborn Infant; Oncogenic; Open Reading Frames; Outcome; Outcome Assessment; Patients; Peptides; Persons; Phenotype; Production; Pulmonary Heart Disease; Rare Diseases; Recovery; Research; Respiratory Tract Infections; Risk Reduction; Role; Serum; Severities; Source; Structure; Symptoms; System; Technology; Time; Tropism; Variant; Vascular Endothelium; Viral Vector; Virus; Work; X-linked myotubular myopathy; adenoviral mediated; body system; cell type; cost; design; enzyme activity; enzyme replacement therapy; gene therapy; gene transfer vector; improved; in vivo; interest; intravenous administration; loss of function; manufacture; mouse model; physical symptom; repaired; transgene expression; vector

ABSTRACT Mucopolysaccharidoses type I (MPS I) is a devastating lysosomal storage disorder that affects approximately 1 in 100,000 newborns. MPS I is characterized by mutations in the α-L-Iduronidase (IDUA) gene that lead to an accumulation of glycosaminoglycans in lysosomes. While treatment is available, it is non-curative, monetarily costly, and time-consuming. To this end, alternative therapies to MPS I have been highly sought after and one such approach is gene therapy. While several vector systems have been explored in the pursuit of a gene therapy treatment for MPS I, adenoviral vectors have been highly understudied. Adenoviral vectors offer several advantages to other vectors such as the ability to transduce both replicating and non-replicating cells, the inability to integrate into the host genome without the use of gene editing technology, and recent modifications leading to the ability to transduce previously unreachable cell types. Thus, investigating the consequences of adenoviral mediated gene therapy for MPS I could lead to new treatment avenues for MPS I. In order to understand the consequence(s) of adenoviral gene therapy for MPS I, I will employ the MPS I murine model and develop an adenoviral vector to deliver the open reading frame for IDUA. I plan to modify our vector using a myeloid-binding peptide to favorably transduce endothelial cells. I hypothesize that a non-liver cellular source can subserve the role of cellular production of IDUA and traverse liver targeting, and, through employment of gene editing technology, long-term correction can be achieved. I will address this hypothesis and achieve the goals of this proposal by employing a myeloid binding peptide modified adenoviral vector expressing IDUA and using in vivo assays to determine IDUA levels in serum post-infection. I will also determine the ability to achieve long-term correction through the use the gene editing technology CRISPR/Cas9. The findings of this proposal will better determine the feasibility of utilizing modified adenoviral vectors as gene therapy vessels and as a treatment method for MPS I and other inherited, monogenic disorders.

抽象的 I 型粘多糖贮积症 (MPS I) 是一种毁灭性的溶酶体贮积症，影响大约 1 100,000 名新生儿中。 MPS I 的特点是 α-L-艾杜糖醛酸酶 (IDUA) 基因突变，导致 糖胺聚糖在溶酶体中的积累。虽然可以进行治疗，但它在经济上是非治愈性的 既昂贵又耗时。为此，MPS I 的替代疗法受到高度追捧，其中一种 这种方法就是基因疗法。虽然在基因治疗的过程中已经探索了几种载体系统 对于 MPS I 的治疗，腺病毒载体的研究还很不足。腺病毒载体提供了多种 与其他载体相比的优势，例如能够转导复制和非复制细胞， 无需使用基因编辑技术即可整合到宿主基因组中，而最近的修改导致 转导以前无法到达的细胞类型的能力。因此，研究腺病毒的后果 MPS I 介导的基因治疗可能会为 MPS I 带来新的治疗途径。 对于 MPS I 腺病毒基因治疗的后果，我将采用 MPS I 小鼠模型并开发一种 腺病毒载体为 IDUA 提供开放阅读框。我计划使用骨髓结合修饰我们的载体 肽有利地转导内皮细胞。我假设非肝细胞来源可以促进 IDUA 的细胞产生和穿越肝脏靶向的作用，以及通过使用基因 编辑技术，可实现长期校正。我将解决这个假设并实现 通过使用表达 IDUA 的骨髓结合肽修饰的腺病毒载体来实现该提案的目标 使用体内测定法测定感染后血清中的 IDUA 水平。我也会确定实现的能力 通过使用基因编辑技术CRISPR/Cas9进行长期校正。本提案的调查结果 将更好地确定利用修饰的腺病毒载体作为基因治疗容器和作为 MPS I 和其他遗传性单基因疾病的治疗方法。