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: 9607812
• 负责人: Diane Ignar
• 金额: $ 21.35万
• 依托单位: OSTREA BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-04 至 2018-12-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9607812
• 关键词: Novel; nanoparticle; based; enzyme; replacement

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.

抽象的 意义：总体患病率〜1：5-7000活出生，溶酶体储存疾病（LSD）为课程 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，通常在生命的前二十年是致命的。中枢神经系统病理存在 但是，目前约有75％的LSD销售酶替代疗法（ERT）对LSD无效 具有明显的CNS病理学，因为在治疗系列的大脑中可忽略不计 酶的浓度。在体细胞组织中摄取效率低下的酶，中和抗体发育， 成本效益差，每周静脉输注是其他次优属性。猎人综合症，引起 通过1：100,000的男性出生的X连锁iduronate-2-sulfatase（I2S）突变与严重有关 神经病理学和广泛的体细胞病理学。 Elaprase®，人类重组I2S，没有解决 CNS病理学却提供给所有患者，每年的销售额接近6亿美元。鞘内I2是 创新：Neuronano Pharma提出的提案，以开发创新的聚合物 - I2S的基于i2s的纳米颗粒公式，该公式将在地下递送以实现热脑 I2的水平。该产品将对猎人综合征患者产生变革性影响，并扩大 有望将技术应用于酶突变引起的其他LSD。方法： 亚历山大·卡巴诺夫（Alexander Kabanov）博士的初步数据，其中包含酶的图片表明大脑 这些配方可以实现递送，免受抗体反应的保护以及可以忽略不计的毒性。 在UNC结构生物学中心表达和纯化后，I2将纳入 纳米级核心螺旋波利离子配合物（图片），在水性条件下通过 将阴离子酶与由阳离子块组成的共聚物混合后的静电相互作用 和亲水性非离子阻滞。 Kabanov博士和该领域的专家Judy Riffle博士将担任 顾问。 I2S PIC公式将在物理特性（酶）方面表征 活性，细胞毒性，溶酶体定位和大脑水平。将选择两个公式 William Banks博士（VA Puget Sound Health Carey系统）的药代动力学表征，血液大脑 障碍专家。除了自己的实验室设施外，NNP还可以通过 UNC纳米药物表征核心设施。预期结果：优化的I2S图片将是 鉴定出将在脑实质和溶酶体中至少增加五倍的I2倍 释放I2和至少50％SC注射后血清生物利用度。延长血清T1/2和宽阔的体细胞 与游离i2s相比，组织的吸收也是可取的。在第二阶段，I2S图片将在I2S淘汰赛中进行测试 小鼠证明大脑中的酶活性增强，对神经病理学的有效性和保护 免疫反应。优化的I2S图片将在预先印度GLP毒理学中进行缩放和测试。