Translational and clinical studies targeting y-globin modulation

针对 y 珠蛋白调节的转化和临床研究

• 批准号: 8467857
• 负责人: DAVID A WILLIAMS
• 金额: $ 150.19万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467857
• 关键词: 5 year old; Acute Pain; Admission activity; Adoption; Adult; Africa; Age; Applications Grants; Arabs; Area; Benign; Biological; Biology; Birth; Boston; Caring; Cell Count; Cell Therapy; Chemicals; Child; Childhood; Clinical; Clinical Research; Clinical Trials; Developed Countries; Developing Countries; Development; Diagnosis; Discipline; Disease; Environment; Feasibility Studies; Fetal Hemoglobin; Foundations; Genetic; Globin; Goals; Haplotypes; Health Expenditures; Health Services; Healthcare Fees; Hematology; Hemoglobin F Disease; Hemoglobinopathies; Histone Deacetylase Inhibitor; Hospitals; Human; Immunization; Individual; Infant Mortality; Institutes; Institution; Life Expectancy; Metabolism; Methods; Minority; Modality; Molecular; Morbidity - disease rate; Nature; Oral; Organ; Patients; Pediatric Hospitals; Penicillins; Pharmaceutical Preparations; Phenotype; Pilot Projects; Prophylactic treatment; Public Health; Research; Research Personnel; Sickle Cell Anemia; Supportive care; Symptoms; Technology; Toxic effect; Translational Research; Treatment Cost; United Nations; United States; Woman; World Health Organization; base; burden of illness; chronic pain; cost; fetal; gamma Globin; gene therapy; improved; innovation; migration; mortality; multidisciplinary; novel therapeutics; nutrition; population based; pre-clinical; programs; research clinical testing; sickling; skills; translational study

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.

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。SCD对美国的公共卫生造成了重大负担，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 孩子们非常高。拟议的合作项目的目标是开发治疗SCD疾病的新方法，并认识到近期内，涉及适用于美国的遗传疗法的高科技方法将需要被利用靶向口服药物的廉价低科技方法所取代，这些方法也可以在世界的发展中地区使用。因此，本申请的重点是利用最先进的化学和生物学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。该计划旨在利用最近的科学突破，快速发展的技术和几个优秀研究机构的环境来推动这种疾病的转化议程。这个多学科资助申请的首要主题是利用创新的科学方法来确定并投入临床研究新的治疗方式，调节γ-珠蛋白的表达。有三个项目：i）整合更传统的分子血液学方法、转化研究和来自代谢领域的方法以鉴定γ-珠蛋白的新诱导剂; ii）调节Bell 1A表达以增加HbF; iii）鉴定具有最佳选择性的HDAC抑制剂以最大化γ-珠蛋白表达的诱导同时最小化毒性。利用高度复杂的转化研究计划的既定基础，该计划专注于临床基因和细胞治疗，并锚定转化研究技能发展核心，来自波士顿儿童医院（CHB）SCD和球蛋白生物学世界知名高级研究人员的建议，并利用新的科学专业知识，以前不专注于CHB的血红蛋白病，布里格姆妇女医院和布罗德研究所的科学发现迅速迁移从这个计划到临床前，然后临床试验是可能的。