Phenotypic effects of brain-directed enzyme therapy for Sanfilippo B syndrome

脑定向酶疗法对 Sanfilippo B 综合征的表型影响

• 批准号: 9234075
• 负责人: PATRICIA I DICKSON
• 金额: $ 31.03万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234075
• 关键词: Address; Adult; Affect; Alpha Cell; Behavioral; Binding; Binding Sites; Brain; Canis familiaris; Cell Therapy; Cells; Child; Chimeric Proteins; Circadian Rhythms; Cognitive; Data; Destinations; Deterioration; Development; Disease; Enzymes; FDA approved; Genes; Glycosaminoglycans; Human; Hypothalamic structure; IGF Type 2 Receptor; IGF2R gene; Impairment; In Vitro; Injection of therapeutic agent; Insulin-Like Growth Factor II; Intraventricular; Lead; Lysosomal Storage Diseases; Lysosomes; Mannose; Manufactured form; Mediating; Modeling; Mucopolysaccharidoses; Mus; Neurologic; Organ; Pathology; Patients; Peptide Fragments; Phenotype; Phosphorylation; Process; Production; Property; Proteins; Quality of life; Recombinants; Research; Site; Sleep; Sleep disturbances; Stem cells; Symptoms; Syndrome; System; Therapeutic; Time; Visceromegaly; Visual impairment; alpha-n-acetylglucosaminidase; behavior test; clinical development; enzyme deficiency; enzyme replacement therapy; enzyme therapy; gene therapy; hearing impairment; improved; in vivo; lateral ventricle; mannose 6 phosphate; mouse model; neurobehavior; neurobehavioral; neuropathology; novel therapeutics; preclinical development; public health relevance; receptor; receptor binding; reduce symptoms; scavenger receptor; success; therapeutic enzyme; trafficking; treatment effect; uptake

 DESCRIPTION (provided by applicant): Sanfilippo B syndrome is a devastating lysosomal storage disorder due to deficiency of the enzyme alpha-N- acetylglucosaminidase (NAGLU). Most therapeutic approaches that have been used or proposed for the lysosomal storage diseases that are due to missing enzymes involve replacing that enzyme into the deficient host in some way- either using wild-type donor stem cells (which provide the missing enzyme), gene therapy to deliver the gene that encodes the enzyme, or by recombinant enzyme administration. All of these depend on the special property of lysosomal enzymes that is made possible by the mannose 6-phosphate receptor system: lysosomal enzymes can be secreted by a cell, taken up by another cell via mannose 6-phosphate receptors, and shuttled to lysosomes where they can act to reduce stored substrate. Unfortunately for people affected with Sanfilippo B syndrome, NAGLU does not contain sufficient mannose 6-phosphate when expressed recombinantly, so that cellular uptake and lysosomal targeting never take place. We have generated a fusion construct of NAGLU and a portion of insulin-like growth factor 2 (IGF2). The natural scavenger receptor for IGF2 is the mannose 6-phosphate receptor (though it binds at a different site than does mannose 6- phosphate). Our preliminary in vitro and in vivo data show that recombinant human NAGLU-IGF2 is active, enters cells, and can reduce lysosomal storage with high efficiency. The next step, which this proposal seeks to address, is to determine whether recombinant human NAGLU-IGF2 will improve the Sanfilippo B phenotype, which is one of progressive cognitive deterioration. In this project, we propose to study this potential new therapy in vivo, to determine whether it improves neurobehavior, physical disease, and survival. The results will tell us whether recombinant NAGLU-IGF2 can serve as effective enzyme therapy for this devastating disease. Results may also have implications for gene and cell therapy approaches for Sanfilippo B, which might be made more effective with the use of IGF2-mediated lysosomal targeting.

 描述（由申请人提供）：Sanfilippo B 综合征是一种由于缺乏α-N-乙酰氨基葡萄糖苷酶（NAGLU）而导致的破坏性溶酶体贮积症。大多数已用于或提议用于治疗由于酶缺失而导致的溶酶体贮积症的治疗方法涉及以某种方式将该酶替换到缺陷宿主体内——使用野生型供体干细胞（提供缺失的酶）、基因治疗以传递编码该酶的基因，或通过重组酶施用。所有这些都取决于溶酶体酶的特殊性质，这种特殊性质是由 6-磷酸甘露糖受体系统实现的：溶酶体酶可以由一个细胞分泌，通过 6-磷酸甘露糖受体被另一个细胞吸收，并穿梭到溶酶体，在那里它们可以发挥作用以减少储存的底物。不幸的是，对于 Sanfilippo B 综合征患者来说，NAGLU 在重组表达时不含有足够的甘露糖 6-磷酸，因此细胞摄取和溶酶体靶向永远不会发生。我们已经生成了 NAGLU 和部分胰岛素样生长因子 2 (IGF2) 的融合构建体。 IGF2 的天然清道夫受体是 6-磷酸甘露糖受体（尽管它与 6-磷酸甘露糖的结合位点不同）。我们的初步体外和体内数据表明，重组人NAGLU-IGF2具有活性，进入细胞，并且可以高效减少溶酶体储存。该提案寻求解决的下一步是确定重组人 NAGLU-IGF2 是否会改善 Sanfilippo B 表型，这是一种进行性认知恶化的表型。在这个项目中，我们建议在体内研究这种潜在的新疗法，以确定它是否可以改善神经行为、身体疾病和生存。结果将告诉我们重组 NAGLU-IGF2 是否可以作为这种破坏性疾病的有效酶疗法。结果也可能对 Sanfilippo B 的基因和细胞治疗方法产生影响，使用 IGF2 介导的溶酶体靶向可能会变得更有效。