Novel nanoparticle-based enzyme replacement therapy for Hunter Syndrome

针对亨特综合症的新型纳米颗粒酶替代疗法

• 批准号: 9407964
• 负责人: Diane Ignar
• 金额: $ 1.02万
• 依托单位: NEURO10-9 PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-05 至 2017-12-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9407964
• 关键词: Address; Alpha Particles; Antibody Formation; Antibody Response; Behavioral; Biological Availability; Biological Preservation; Birth; Blood; Blood - brain barrier anatomy; Brain; Cations; Cessation of life; Characteristics; Childhood; Complex; Core Facility; Data; Development; Disease; Disease model; Drug Kinetics; Electrostatics; Enzymes; Equipment; Evaluation; Family; Formulation; Functional disorder; Generations; Goals; Half-Life; Healthcare Systems; Hour; Human; Immune response; Impaired cognition; Intravenous infusion procedures; Knockout Mice; Laboratories; Life; Link; Live Birth; Lysosomal Storage Diseases; Lysosomes; Mental Retardation; Mucopolysaccharidosis II; Mus; Mutation; Nerve Degeneration; PC12 Cells; Particle Size; Pathology; Patients; Penetration; Peptide Hydrolases; Pharmacology; Phase; Polymers; Prevalence; Property; Proteins; Quality of life; Recombinants; Sales; Seizures; Serum; Subcutaneous Injections; Symptoms; Technology; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; aqueous; base; bone; brain parenchyma; copolymer; cost effectiveness; cytotoxicity; enzyme activity; enzyme replacement therapy; experience; hydrophilicity; iduronate-2-sulfatase; improved outcome; indexing; infancy; innovation; interest; laboratory facility; male; nanomedicine; nanoparticle; nanoscale; neuropathology; neutralizing antibody; novel; polyion; pre-clinical; progressive neurodegeneration; scale up; sound; structural biology; subcutaneous; uptake

ABSTRACT Significance: With overall prevalence of ~1:5-7000 live births, lysosomal storage diseases (LSD) as a class are one of the most common childhood diseases. LSD are caused by lysosomal dysfunction, mainly due to lysosomal enzyme mutations, and are usually fatal in the first two decades of life. CNS pathology is present in ~75% of LSD, however, currently marketed enzyme replacement therapy (ERT), is not effective for LSD with significant CNS pathology because negligible enzyme levels are achieved in brain at therapeutic serum concentrations of enzyme. Inefficient enzyme uptake in somatic tissues, neutralizing antibody development, poor cost-effectiveness, and weekly IV infusions are other suboptimal attributes. Hunter Syndrome, caused by X-linked iduronate-2-sulfatase (I2S) mutations in 1:100,000 male births, is associated with severe neuropathology and broad somatic tissue pathology. Elaprase®, human recombinant I2S, does not address CNS pathology yet is offered to all patients and has sales approaching $600M yearly. Intrathecal I2S is currently in development. Innovation: NeuroNano Pharma proposes to develop an innovative polymer- based nanoparticle formulation of I2S which will be delivered subcutaneously to achieve therapeutic brain levels of I2S. This product will have a transformative impact on Hunter Syndrome patients and, by extension, holds promise for application of the technology to other LSD caused by enzyme mutations. Approach: Preliminary data from Dr. Alexander Kabanov’s laboratory with PICs containing enzymes shows that brain delivery, protection from antibody response, and negligible toxicity can be achieved with these formulations. After expression and purification at the UNC Center for Structural Biology, I2S will be incorporated into nanoscale core-shell polyion complexes (PICs) which form spontaneously in aqueous conditions via electrostatic interactions upon mixing of the anionic enzyme with a copolymer consisting of a cationic block and a hydrophilic nonionic block. Dr. Kabanov and Dr. Judy Riffle, experts in this field, will serve as consultants. I2S PIC formulations will be characterized with respect to physicochemical properties, enzyme activity, cytotoxicity, lysosome localization and brain levels. Two formulations will be selected for full pharmacokinetic characterization by Dr. William Banks (VA Puget Sound Health Care System), a blood brain barrier expert. In addition to its own laboratory facilities, NNP has access to all necessary equipment through the UNC Nanomedicines Characterization Core Facility. Expected Results: An optimized I2S PIC will be identified that will achieve at least a five-fold increase of I2S in brain parenchyma and lysosomes compared to free I2S and at least 50% serum bioavailability after SC injection. Extended serum t1/2 and broad somatic tissue uptake compared to free I2S is also desirable. In phase II, the I2S PIC will be tested in I2S knockout mice to demonstrate enhanced enzyme activity in the brain, efficacy against neuropathology, and protection from immune response. An optimized I2S PIC will be scaled up and tested in pre-IND GLP toxicology.

摘要 意义：总体患病率约为1：5-7000活产，溶酶体贮积病（LSD）作为一类 是最常见的儿童疾病之一。LSD是由溶酶体功能障碍引起的，主要是由于 溶酶体酶突变，并且通常在生命的前二十年是致命的。存在CNS病理学 然而，在约75%的LSD中，目前市售的酶替代疗法（ERT）对LSD无效 具有显著的CNS病理学，因为在治疗血清中脑中达到可忽略的酶水平 酶的浓度。体细胞组织中酶吸收效率低，中和抗体产生， 成本效益差，每周IV输注是其他次优属性。亨特氏综合症，由 X连锁艾杜糖醛酸-2-硫酸酯酶（I2 S）突变在1：100，000的男性出生中，与重度 神经病理学和广泛的躯体组织病理学。Elaprase®，人重组I2 S，不解决 中枢神经系统病理学还提供给所有患者，每年的销售额接近6亿美元。鞘内I2 S是 目前正在开发中。创新：NeuroNano Pharma提议开发一种创新的聚合物- 基于I2 S的纳米颗粒制剂，其将皮下递送以实现治疗性脑 I2 S的水平。该产品将对亨特氏综合症患者产生变革性影响，并进一步推广， 有望将该技术应用于其他由酶突变引起的LSD。方法： 来自亚历山大卡巴诺夫博士实验室的含有酶的PIC的初步数据显示， 用这些制剂可以实现递送、防止抗体应答和可忽略的毒性。 I2 S将在THEORY Center for Structural Biology中表达和纯化后，掺入到 纳米级核-壳聚离子复合物（PIC），其在水性条件下通过 当阴离子酶与由阳离子嵌段组成的共聚物混合时的静电相互作用 和亲水性非离子嵌段。Kabanov博士和Judy Riffle博士是该领域的专家，将担任 顾问。I2 S PIC制剂将在理化性质、酶 活性、细胞毒性、溶酶体定位和脑水平。将选择两种制剂进行全面研究。 由William Banks博士（VA Puget Sound Health Care System）进行药代动力学表征， 屏障专家除了自己的实验室设施外，NNP还可以通过以下途径获得所有必要的设备： 纳米医学表征核心设施。预期结果：优化的I2 S PIC将 确定，将实现脑实质和溶酶体中的I2 S至少增加5倍， 至游离I2 S和至少50%的血清生物利用度。延长血清t1/2和广泛的躯体 与游离I2 S相比，组织吸收也是所希望的。在第二阶段，I2 S PIC将在I2 S敲除中进行测试 小鼠，以证明脑中酶活性增强、对神经病理学的功效和保护作用 免疫反应。优化的I2 S PIC将在IND前GLP毒理学中进行规模放大和检测。