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，具体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-艾杜糖酸酶缺乏所致 (IDUA) 酶导致糖胺聚糖 (GAG) 的全系统储存，而 Hurler 综合征， 这代表了最严重程度的 IDUA 缺乏和症状，出现在第一年 神经发育停滞和随后的退化的生活，我也经历过其他形式的 MPS 中枢神经系统受累，包括硬脑膜增生、椎管狭窄和脊髓病。所有形式的 MPS I 均有表现。 由滑膜肥大和炎症引起的疼痛性退行性关节疾病，以及关节异常 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扩张治疗 MPS I，或者干细胞移植。 (SCT) 或静脉酶替代疗法 (ERT) 使用重组人 IDUA，减少疾病 减轻 MPS I 患者的负担并延长其预期寿命，但代表 SCT 的不完整疗法。 免疫功能低下、移植物抗宿主病、移植不完全或死亡的重大风险。 必须在患者的一生中重复给药并且不会穿过血脑屏障， 使其无法治疗接受 SCT 治疗的 Hurler 患者，即使是具有完全造血能力的患者。 植入和正常血液 IDUA 水平，患有严重的认知缺陷并需要康复 SCT 和 ERT 都不能改善关节挛缩和骨关节炎，使患者每天都感到疼痛， 因此，显然有必要开发一种单次治疗。 MPS I 可安全、持久、完全恢复全身 IDUA 水平，特别是中枢神经系统和 关节，以纠正多个关键受影响组织的症状，这种必要性变得更加紧迫。 越来越多的 MPS I 通过新生儿筛查在新生儿期被发现，这提供了一个机会 提供早期治疗并预防所有器官系统出现症状。 犬 MPS I 模型，用于评估多模式基因治疗方法，同时治疗 脑池内、关节内和静脉内腺相关病毒载体的组合，携带 该提案的目标 1 将研究这种新方法安全的能力。 产生IDUA酶的CNS表达，消除GAG储存，并转化为改善 该提案的目标 2 将评估大脑成像和认知功能的异常。 IDUA酶，清除关节滑膜和软骨中储存的GAG，改善关节 形态、炎症减少和韧带强度正常化， 本研究还将评估肝和心脏组织中的底物减少和病理学。 生成重要的关键数据，为后续多模式基因替代疗法的临床试验提供信息 human MPS I，解决受影响患者面临的未满足的需求。