Combination Gene Therapy for Treatment of Canine Mucopolysaccharidosis Type I

治疗犬 I 型粘多糖贮积症的组合基因疗法

• 批准号: 10582337
• 负责人: RAYMOND YU JEANG WANG
• 金额: $ 70.88万
• 依托单位: CHILDREN'S HOSPITAL OF ORANGE COUNTY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-05 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582337
• 关键词: Activities of Daily Living; Address; Affect; Aorta; Biochemistry; Biological Models; Biomechanics; Blood; Blood - brain barrier anatomy; Brain; Brain imaging; Canis familiaris; Cardiac; Cardiomyopathies; Caring; Cartilage; Central Nervous System; Central Nervous System Diseases; Cerebral cortex; Cessation of life; Child; Chondrocytes; Circulation; Clinical Trials; Clinical assessments; Cognitive; Cognitive deficits; Contracture; Data; Deformity; Degenerative polyarthritis; Dependovirus; Deterioration; Development; Dilatation - action; Disease; Disease Progression; Dose; Dysplasia; Early treatment; Engraftment; Enzymes; Future; Genes; Genetic Diseases; Glycosaminoglycans; Heart; Hematopoietic Stem Cell Transplantation; Hepatic; Hepatosplenomegaly; Histopathology; Human; Hyperplasia; Hypertrophy; IGF Type 2 Receptor; Image; Imaging Techniques; Immobilization; Immune Tolerance; Immunocompromised Host; Impaired cognition; Infant; Inflammation; Infusion procedures; Injections; Intellectual functioning disability; Intravenous; Joints; Knowledge; L-Iduronidase; Life; Life Expectancy; Ligaments; Liver; Long-Term Effects; Magnetic Resonance Imaging; Methods; Modality; Modeling; Morphology; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis I H; Mucopolysaccharidosis I S; Neonatal Screening; Nerve Degeneration; Neurocognition; Neurocognitive; Neurons; Pain; Pathology; Patients; Penetration; Pennsylvania; Peripheral; Persons; Phenotype; Play; Positioning Attribute; Proliferating; Property; Protocols documentation; Quality of life; Reaction; Recombinants; Recommendation; Refractory; Rehabilitation therapy; Research Personnel; Risk; Role; Satellite Viruses; Sepsis; Services; Spinal Canal; Spinal Cord Diseases; Spleen; Stem cell transplant; Stenosis; Structure; Symptoms; Synovial Membrane; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Translating; Universities; Venous; Work; adeno-associated viral vector; arthropathies; biomarker identification; biomechanical test; body system; burden of illness; canine model; cognitive function; combination gene therapy; daily pain; design; disease phenotype; early childhood; enzyme activity; enzyme replacement therapy; experience; gene replacement; gene replacement therapy; gene therapy; graft vs host disease; hematopoietic engraftment; immunoreaction; improved; joint inflammation; liver imaging; multimodality; neonatal period; neonate; neuroimaging; neuropathology; novel; novel strategies; pre-clinical; prevent; response; restoration; screening panel; symptomatology; tandem mass spectrometry; tractography; transgene expression; treatment response; white matter

MPS I, historically known as Hurler, Hurler-Scheie, and Scheie syndromes depending upon degree of central nervous system (CNS) involvement and velocity of disease progression, is a deficiency of the α-L-iduronidase (IDUA) enzyme resulting in pansystemic storage of glycosaminoglycans (GAGs). While Hurler syndrome, which represents the most severe degree of IDUA deficiency and symptomatology, presents in the first year of life with neurodevelopmental stagnation and subsequent regression, the other forms of MPS I also experience CNS involvement with dural hyperplasia, spinal canal stenosis, and myelopathy. All forms of MPS I manifest painful, degenerative joint disease caused by synovial hypertrophy and inflammation, and abnormalities of chondrocyte proliferation and matrix synthesis. Other MPS I symptoms include hepatosplenomegaly, cardiomyopathy, valve dysplasia, and aortic root dilatation. Treatments for MPS I, either stem cell transplant (SCT) or intravenous enzyme replacement therapy (ERT) with recombinant human IDUA, reduce disease burden and extend life expectancy of MPS I patients, but represent incomplete therapies. SCT poses significant risks of immunocompromise, graft-versus-host disease, incomplete engraftment, or death. ERT must be administered repeatedly for the patient’s entire lifetime and does not cross the blood-brain barrier, rendering it incapable of treating CNS disease. SCT-treated Hurler patients, even with full hematopoietic engraftment and normal blood IDUA levels, suffer significant cognitive deficits and require rehabilitative services. Neither SCT nor ERT ameliorate joint contractures and osteoarthritis, leaving patients with daily pain, immobility, and reduced quality of life. Therefore, there is a clear necessity to develop a single-session therapy for MPS I which safely, durably, and fully restores IDUA levels throughout the body especially the CNS and joints, to correct symptoms in multiple key affected tissues. This necessity takes on additional urgency as increasingly, MPS I is identified in the neonatal period through newborn screening, presenting an opportunity to provide early treatment and prevent onset of symptoms throughout all organ systems. This study utilizes the canine MPS I model to evaluate a multimodal gene therapy approach, simultaneously treating with combinations of intracisternal, intra-articular, and intravenous adeno-associated virus vector carrying copies of the normal canine IDUA gene. Aim 1 of this proposal will study the ability of this novel approach to safely generate CNS expression of IDUA enzyme, eliminate GAG storage, and translate to improvement of abnormalities in brain imaging and cognitive function. Aim 2 of this proposal will evaluate for expression of IDUA enzyme, clearance of GAG storage in joint synovium and cartilage, and improvement of joint morphology, reduction of inflammation, and normalization of ligamentous strength. Enzyme expression, substrate reduction, and pathology will also be assessed in hepatic and cardiac tissues. This study will generate essential key data informing subsequent clinical trials of multimodal gene replacement therapy in human MPS I, addressing the unmet need faced by affected patients.

MPS I，历史上称为Hurler、Hurler-Scheie和Scheie综合征，取决于中枢神经系统的程度。 神经系统（CNS）受累和疾病进展速度，是α-L-艾杜糖醛酸酶缺乏 （IDUA）酶导致糖胺聚糖（GAG）的全系统储存。当Hurler综合征， 这代表了IDUA缺乏症和糖尿病的最严重程度，出现在第一年， 神经发育停滞和随后倒退的生活，我也经历过其他形式的MPS 中枢神经系统累及硬脑膜增生、椎管狭窄和脊髓病。所有形式的MPS I表现 由滑膜肥大和炎症引起的疼痛性退行性关节疾病，以及 软骨细胞增殖和基质合成。其他MPS I症状包括肝脾肿大， 心肌病、瓣膜发育不良和主动脉根部扩张。MPS I的治疗，无论是干细胞移植 (SCT)或用重组人IDUA进行静脉内酶替代疗法（ERT）， 增加MPS I患者的负担并延长预期寿命，但代表不完整的治疗。SCT姿势 免疫功能低下、移植物抗宿主病、植入不完全或死亡的显著风险。ERT 必须在患者的整个生命周期内重复给药并且不能穿过血脑屏障， 使其不能治疗CNS疾病。SCT治疗的Hurler患者，即使造血功能完全恢复， 移植和正常血液IDUA水平，遭受显著的认知缺陷，需要康复治疗。 服务SCT和ERT都不能改善关节挛缩和骨关节炎，使患者每天都有疼痛， 不动，生活质量下降。因此，有一个明确的必要性，以发展一个单一的会议治疗 对于MPS I，安全、持久和完全恢复全身尤其是CNS的IDUA水平， 关节，以纠正多个关键受影响组织的症状。这一必要性更加紧迫， 越来越多的MPS I是在新生儿期通过新生儿筛查确定的，这为 提供早期治疗并预防所有器官系统的症状发作。这项研究利用了 犬MPS I模型，以评估多模式基因治疗方法，同时用 脑池内、关节内和静脉内腺相关病毒载体的组合， 正常犬IDUA基因本提案的目标1将研究这种新方法安全地 产生IDUA酶的CNS表达，消除GAG储存，并转化为改善 大脑成像和认知功能异常。本提案的目标2将评估以下表达 IDUA酶，清除关节滑膜和软骨中的GAG储存，并改善关节 形态学、炎症减少和韧带强度正常化。酶表达， 还将在肝和心脏组织中评估底物减少和病理学。本研究将 生成必要的关键数据，为随后的多模式基因替代疗法的临床试验提供信息， 人MPS I，解决受影响患者面临的未满足的需求。