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Novel therapeutic gene editing to induce fetal hemoglobin for sickle cell disease

诱导胎儿血红蛋白治疗镰状细胞病的新型治疗性基因编辑

基本信息

批准号：
10587901
负责人：
Akshay Sharma
金额：
$ 118.3万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587901
关键词：
AMD3100 Acute Pain Adult Affect Allogenic American Attention Autologous BCL11A gene Binding Bioethics Consultants Biological Assay Biological Markers Birth Blood Bone Marrow CD34 gene CRISPR/Cas technology Caring Cell Differentiation process Cells Cessation of life Chromosomal Rearrangement Clinical Clinical Research Clinical Trials Communities Complex Data Deterioration Development Disease Education Engineering Engraftment Enhancers Erythrocytes Erythroid Erythropoiesis Euthanasia Exhibits Fetal Hemoglobin Functional disorder Future Genes Genetic Genetic Diseases Genetic Transcription Globin Good Manufacturing Process Guide RNA Hematopoietic stem cells Hemoglobin Human Immune Immunodeficient Mouse Impairment In Vitro Individual Informed Consent Infusion procedures Laboratory Scientists Lead Life Longevity Mediating Medical Missense Mutation Modification Molecular Monitor Multiple Organ Failure Mus Mutation Detection Normal Cell Nuclear Localization Signal Organ Outcome Pain Parents Participant Patients Perinatal Pharmaceutical Preparations Pharmacology Study Polymers Premature Mortality Process Process Assessment Production Protocols documentation Publishing Quality Control Quality of life Repressor Proteins Research Ribonucleoproteins Running Safety Saint Jude Children&apos s Research Hospital Sickle Cell Anemia Sickle Cell Trait Sickle Hemoglobin Specific qualifier value Technology Testing Therapeutic Toxic effect Toxicology Transcription Repressor Transfection Translating Transplantation Variant Work Xenograft procedure analytical method bench to bedside beta Globin biophysical properties chronic pain clinical practice curative treatments debilitating pain design early phase clinical trial efficacy evaluation erythroid differentiation experience feasibility testing first-in-human gene therapy genetic variant genome editing genome-wide genotoxicity hematopoietic cell transplantation improved in vivo indexing insertion/deletion mutation manufacture manufacturing process multidisciplinary novel novel therapeutics off-target mutation patient oriented polymerization pre-clinical premature process optimization promoter research study safety assessment scale up sickling stem cell growth stem cell therapy stem cells therapeutic gene

项目摘要

PROJECT SUMMARY Despite advances in the medical care of sickle cell disease (SCD), most patients continue to experience debilitating pain, poor quality of life, progressive organ deterioration, and premature death. We are developing a novel, potentially curative therapy for SCD based on genome editing of autologous hematopoietic stem cells (HSCs) to induce the production of fetal hemoglobin (HbF, 22) in red blood cells (RBCs). Natural genetic variants can generate high levels of HbF that alleviate or eliminate the pathophysiology of SCD. Our published studies show that one of these variants can be recreated by Cas9-mediated disruption of a -globin gene promoter motif recognized by BCL11A, a transcriptional repressor protein that drives the normal perinatal switch from -globin to -globin expression. New preliminary data show that transfection of normal or SCD patient donor CD34+ cells with ribonucleoprotein (RNP) complex consisting of Cas9 and guide RNA (gRNA) targeting the BCL11A binding motif, followed by xenotransplantation into immunodeficient mice, consistently achieved ≥70% on-target editing in bone marrow-repopulating HSCs, with no off-target mutations detected by rigorous genome- wide activity analysis at a sensitivity of 0.1%. The modified HSCs generated RBCs in vivo with >30% pancellular HbF and 18-31% sickling in 2% O2, compared to <5% HbF and 62-71% sickling in unmodified control RBCs (P<0.0001). We will now translate our findings “from bench to bedside” by designing and carrying out a first-in- human clinical study, termed St. Jude Autologous Genome Edited Stem Cells (SAGES1), examining the safety and efficacy of autologous -globin promoter-edited CD34+ cells (drug product SJ-1001) according to 3 Aims. Aim 1 will define the mechanism of action, potency, and safety profile of SJ-1001 through FDA-enabling and exploratory research studies. Aim 2 will establish cGMP clinical scale manufacturing of SJ-1001 by optimizing process development, generating drug product release assays for the clinical trial, and transferring these protocols to the St. Jude current good manufacturing practice (cGMP) facility. Aim 3 will establish and manage the SAGES1 clinical trial to evaluate one-time SJ-1001 infusion as a cure for SCD. This will include the development of an enhanced multidisciplinary informed consent process, safety and efficacy assessments, and post therapy mechanistic studies. Our work has the potential to relieve suffering and extend the lifespan of thousands of patients with severe SCD.

项目总结