Translational and clinical studies targeting y-globin modulation

描述(由申请人提供)： 镰状细胞病是世界上最常见的血红蛋白病，也是最常见的单基因疾病之一。慢性阻塞性肺病在美国构成了主要的公共卫生负担，医疗保健服务的总费用为10亿美元。在全球范围内，死亡率，特别是年轻人的死亡率 孩子们都很高。拟议的合作项目的目标是开发治疗SCD疾病的新方法，认识到短期内，涉及适用于美国的基因疗法的高科技方法将需要被使用靶向口服药物的廉价低技术方法所取代，这些药物也可以在世界发展中地区使用。因此，这一应用的重点是利用最先进的化学和生物方法来增加胎儿血红蛋白的表达，以改善SCD的发病率和治疗成本。拟议的计划寻求利用最近的科学突破、快速进步的技术和几个优秀研究机构的环境来推动这种疾病的翻译议程。这一多学科拨款申请的首要主题是利用创新的科学方法来确定并将调节伽马珠蛋白表达的新治疗模式投入临床研究。有三个项目：i)整合更传统的分子血液学方法、翻译研究和新陈代谢领域的方法，以确定新的γ-珠蛋白诱导剂；ii)调节Bell 1A的表达以增加HBF；iii)寻找具有最佳选择性的HDAC抑制剂，以最大限度地诱导γ-珠蛋白的表达，同时将毒性降至最低。利用波士顿儿童医院(CHB)高度尖端的翻译研究计划的既定基础，该计划专注于临床基因和细胞治疗，并支撑翻译研究技能开发核心，来自世界知名的SCD和波士顿儿童医院(CHB)珠蛋白生物学高级研究员的建议，并利用以前在CHB，布里格姆妇女医院和布罗德研究所并不专注于血红蛋白疾病的新科学专业知识，该计划产生的科学发现有可能迅速转移到临床前，然后临床测试。

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is the most common hemoglobinopathy and one of the most common monogenic diseases in the world. SCD poses a major public health burden in the US with an aggregate charge for health care services of $1 billion. Globally, mortality, particularly in young children is very high. The goal of the proposed collaborative project is to develop new methods to treat SCD disease, with the realization that near term, high tech approaches involving genetic therapies applicable in the US will need to be replaced with inexpensive low-tech approaches utilizing targeted oral drugs that can be also be utilized in the developing areas of the world. Th focus of this application is thus to leverage state-of-the-art chemical and biological approaches to increase the expression of fetal hemoglobin to ameliorate the morbidity and cost of treatment of SCD. The proposed program seeks to take advantage of recent scientific breakthroughs, rapidly advancing technology and the environment of several outstanding research institutions to drive the translational agenda in this disease. The overarching theme of this multidisciplinary grant application is to utilize innovative scientific approaches to identify and put into clinical investigation new therapeutic modalities that modulate gamma-globin expression. There are three projects: i) integrating more traditional molecular hematology approaches, translational research, and approaches from the field of metabolism to identify new inducers of y-globin; ii) modulation of Bell 1A expression to increase HbF; iii) identifying HDAC inhibitors with optimal selectivity to maximize induction of y-globin expression while minimizing toxicity. Utilizing the established foundation of a highly sophisticated translational research program that focuses on clinical gene and cell therapy and anchors the Translational Research Skills Development Core, advice from world-renown senior investigators in SCD and globin biology at Children's Hospital Boston (CHB) and harnessing new scientific expertise not previously focusing on hemoglobinopathies at CHB, Brigham and Women's Hospital and the Broad Institute rapid migration of the scientific discoveries emanating from this program into pre-clinical and then clinical testing is likely.