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) 正在开创一种新疗法，以恢复免疫耐受并阻止白癜风的进行性色素脱失。洛约拉大学 (LUC) 开发了一种诱导热休克蛋白 70 的变体，在预防和治疗自身免疫性白癜风方面具有巨大潜力。这种变体 HSP70iQ435A（称为“CM”）仅对蛋白质进行单一氨基酸修饰，被发现具有疗效，包括树突状细胞 (DC) 的持久耐受性和抑制 T 细胞流入皮肤。使用不同的自发 T 细胞受体转基因白癜风小鼠模型，在预防和治疗环境中，CM DNA 疫苗接种可显着抑制色素脱失。转化为人类后，发现循环和皮肤浸润 DC 中炎症性 CD11b+CD11c+ 树突状细胞亚群的丰度增加，这些树突状细胞负责诱发和延续白癜风。因此，我们假设 CM 同样会干扰人类白癜风的进行性色素脱失。鉴于基础科学研究的实力和创新性以及多种白癜风动物模型所揭示的深远功效，以及临床概念验证的明确路径，我们现在提出 SBIR 第一阶段提案，通过展示以下内容来推进 CM：在临床相关的大型动物白癜风模型中的疗效。具体目标#1：在具有类人皮肤的大型白癜风模型中确定 M 的功效。在 RTX 中，目标 DNA 将被亚克隆到 pUMCV3 中，与原始质粒相比，pUMCV3 是一种适合人类使用和表达的载体。然后将在 pUMVC3 中生成 150 毫克 CM（>99% 纯度），以支持大型动物功效研究以及后续 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 Sinclair 猪（每组 n=6）中进行研究。该模型开发白癜风和黑色素瘤，将用于通过无针喷射注射在模型中测试 CM DNA 的应用，该模型允许在类人皮肤中进行测试，同时测量抗黑色素瘤反应的副作用。通过量化病变区域的变化来衡量疗效。将跟踪局部和全身不良事件，并进行免疫监测，以将早期发现转化为大型动物。这包括对动物血液和皮肤样本中随时间推移采集的树突状细胞和 T 细胞特征进行分析。具体目标#2：准备 CM 以获得 IND 批准。在 RTX，将制定临床方案并计划研究以确定 NOAEL，最终召开 IND 前会议，为 I 期临床研究 IND 批准做准备。对于后续的 GLP 毒理学和安全药理学研究，将在 pUMVC3 中生成 150 mg CM（>99% 纯度）。临床研究人员将接受培训，了解如何使用 CM 及其在临床前环境中的应用，并在必要时处理任何不良事件。我们预计，与盐水对照组相比，CM 将导致白癜风进展减少 > 50%，并且免疫监测将确定皮肤 T 细胞浸润减少 > 50%。