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A Novel Immunotolerizing Therapy for Autoimmune Vitiligo

一种治疗自身免疫性白癜风的新型免疫耐受疗法

基本信息

批准号：
8713488
负责人：
ANDREW Lurie SALZMAN
金额：
$ 22.5万
依托单位：
RADIKAL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8713488
关键词：
Acute Address Adverse effects Adverse event Affect Amino Acids Animal Model Animals Appearance Area Autoimmune Diseases Autoimmune Process Basic Science Blood Chicago Clinical Clinical Investigator Clinical Protocols Clinical Research Clinical Trials Control Groups DNA Dendritic Cells Development Disease Dose Ensure Family suidae Generic Drugs Goals Growth Health Heat-Shock Proteins 70 Human ITGAM gene ITGAX gene Immune Immune Tolerance Immunologic Monitoring Incentives Infiltration Inflammatory Institution Investigation Jet Injections Lead Lesion Measures Medical Memory Modeling Modification Mus Needles Outcome Measure Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Pigments Plasmids Population Preclinical Testing Preparation Prevention Preventive Proteins Protocols documentation Quality of life Relative (related person)Safety Saline Sampling Skin Small Business Innovation Research Grant Social Interaction T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Time Toxic effect Toxicology Training Transgenic Mice Translating United States National Institutes of Health Universities Vaccination Variant Vitiligo Work animal efficacy base clinically relevant design innovation interest man meetings melanocyte melanoma mouse model novel pre-clinical preclinical study professor protein expression public health relevance response safety study scale up skin color vector

项目摘要

DESCRIPTION (provided by applicant): Radikal Therapeutics (RTX) is pioneering a novel therapy to restore immune tolerance and arrest progressive depigmentation in vitiligo. At Loyola University (LUC), a variant to inducible Heat Shock Protein 70 was developed with remarkable potential for the prevention and treatment of autoimmune vitiligo. Carrying only a single amino acid modification to the protein, this variant HSP70iQ435A (designated "CM") was found to have a curative effect involving long-lasting tolerization of dendritic cells (DCs) and inhibition of T ell influx to the skin. Depigmentation was inhibited by CM DNA vaccination to a remarkable extent in both preventive and therapeutic settings using different spontaneous, T cell receptor transgenic mouse models of vitiligo. Translated to humans, the inflammatory CD11b+CD11c+ subset of DCs held responsible for precipitating and perpetuating vitiligo is found in increased abundance among circulating and skin infiltrating DC. We thus hypothesize that the CM will likewise interfere with progressive depigmentation in human vitiligo. Given the strength and innovation of the basic science investigations and the profound efficacy revealed in multiple animal models of vitiligo, and the clear path forward to clinical proof-of-concept, we now propose an SBIR Phase 1 proposal to advance the CM through demonstration of efficacy in a clinically-relevant large animal model of vitiligo. Specific Aim #1: Establish the efficacy of the M in a large vitiligo model with human-like skin. At RTX the DNA of interest will be subcloned into pUMCV3, a vector suited for human use and expression compared to the original plasmid. 150 mg of CM (>99% purity) in pUMVC3 will then be generated to support large animal efficacy studies as well as for follow-on GLP toxicology and safety pharmacology investigations. Our collaborator, Dr. Le Poole (LUC), will carry out studies in Sinclair pigs (n=6 per group). This model, developing vitiligo as well as melanoma, will serve to test CM DNA application by needle-less jet injection in a model that allows for testing in human-like skin while measuring side-effects on anti-melanoma responses. Efficacy is measured by quantifying changes in lesional area. Local and systemic adverse events will be followed, and immune monitoring performed to translate earlier findings to large animals. This includes analysis of dendritic cell and T cell profiles in blood and skin samples taken from the animals over time. Specific Aim #2: Prepare the CM for IND approval. At RTX, a clinical protocol will be prepared and studies planned to determine the NOAEL, culminating in a pre-IND meeting on preparation for IND approval for a Phase I clinical study. For follow-on GLP toxicology and safety pharmacology investigations, 150 mg of CM (>99% purity) in pUMVC3 will be generated. Clinical investigators will be trained in working with the CM and its application in a pre-clinical setting and to manage any adverse events if necessary. We expect that the CM will induce >50% reduction in vitiligo progression relative to the saline control group and that immune monitoring will determine a > 50% reduction in T cell infiltration to the skin.

描述（由申请人提供）：Radikal Therapeutics （RTX）开创了一种新的治疗方法，用于恢复白癜风患者的免疫耐受和阻止进行性色素沉着。在洛约拉大学（LUC），一种诱导热休克蛋白70的变体被开发出来，在预防和治疗自身免疫性白癜风方面具有显著的潜力。这种变体HSP70iQ435A（命名为“CM”）仅携带一个氨基酸修饰蛋白，被发现具有树突状细胞（dc）的持久耐受性和抑制T细胞流入皮肤的疗效。在不同的自发性T细胞受体转基因白癜风小鼠模型中，CM DNA疫苗接种在预防和治疗两种情况下均显著抑制了色素脱失。对于人类来说，在循环和皮肤浸润性DC中，炎症性CD11b+CD11c+亚群的丰度增加，导致白癜风的沉淀和延续。因此，我们假设CM同样会干扰人类白癜风的进行性色素沉着。鉴于基础科学研究的实力和创新，以及在多种白癜风动物模型中显示的深刻疗效，以及临床概念验证的明确路径，我们现在提出SBIR一期提案，通过在临床相关的白癜风大型动物模型中展示疗效来推进CM。具体目标#1：在具有类似人类皮肤的大型白癜风模型中建立M的功效。在RTX，感兴趣的DNA将被亚克隆到pUMCV3中，pUMCV3是一种与原始质粒相比更适合人类使用和表达的载体。然后将生成pUMVC3中的150 mg CM（纯度为99%），以支持大型动物功效研究以及后续的GLP毒理学和安全药理学研究。我们的合作者Le Poole博士（LUC）将在辛克莱猪（每组n=6）中进行研究。这个模型，发展白癜风和黑色素瘤，将用于测试CM DNA的应用，通过无针喷射注射的模型，允许在类似人类的皮肤上进行测试，同时测量抗黑色素瘤反应的副作用。疗效是通过量化病变区域的变化来衡量的。将跟踪局部和全身不良事件，并进行免疫监测，将早期发现转化为大型动物。这包括对长期采集的动物血液和皮肤样本中的树突状细胞和T细胞谱进行分析。具体目标#2：为IND批准准备CM。在RTX，将准备一份临床方案和研究计划，以确定NOAEL，最终在IND前会议上为IND批准I期临床研究做准备。为了进行后续的GLP毒理学和安全药理学研究，将在pUMVC3中生成150 mg CM（纯度为100 - 99%）。临床研究人员将接受培训，在临床前环境中使用CM及其应用，并在必要时管理任何不良事件。我们预计，与生理盐水对照组相比，CM将诱导白癜风进展减少>50%，免疫监测将确定皮肤T细胞浸润减少>50%。