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Identification of novel safe harbors to be used in a gene editing strategy for the treatment of hemophilia A

确定用于治疗 A 型血友病的基因编辑策略的新型安全港

基本信息

批准号：
10459385
负责人：
Jennifer Marie Johnston
金额：
$ 14.65万
依托单位：
SAN JOSE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-04 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459385
关键词：
Adverse effects Alpha Granule Antibodies Antigens Blood Blood Circulation Blood Coagulation Factor Blood Platelets CRISPR/Cas technology Candidate Disease Gene Cells Clinical Clinical Research DNA Development Elements F8 gene Factor VIII General Population Genes Genome Genomics Hematological Disease Hematopoietic System Hematopoietic stem cells Hemophilia A Hemorrhage Immune system Individual Inherited Knock-out Lentivirus Lentivirus Vector Liver Location Mendelian disorder Metabolic Diseases Methods Modification Output Patients Phenotype Physiological Population Procedures Proteins Protocols documentation Recombinants Regulatory Element Risk Site Source System Therapeutic Transgenes Transplantation Treatment Protocols Viral cell type cellular targeting combat cost enzyme replacement therapy functional loss gene therapy genome editing genomic locus homologous recombination ineffective therapies inhibitor lentiviral integration nervous system disorder neutralizing antibody novel patient population pre-clinical promoter prophylactic recombinant antihemophilic factor VIII reduce symptoms repaired self-renewal therapeutic transgene therapeutically effective tool treatment strategy von Willebrand Factor

项目摘要

TITLE Identification of novel safe harbors to be used in a gene editing strategy for the treatment of hemophilia A Project Summary Hemophilia A is a hereditary blood disorder caused by the loss of the functional coagulation factor, factor VIII (fVIII). Prophylactic administration of recombinant fVIII can alleviate blood loss with relatively small amounts of circulating fVIII protein in the bloodstream. However, the current treatment is invasive and expensive, costing upwards of $300,000 per year. In addition, up to 30% of severe hemophilia A patients develop inactivating antibodies to fVIII rendering the current therapy ineffective. As a monogenic disorder, hemophilia A is a promising candidate for gene therapy with a relatively large therapeutic window. Yet, a major barrier to developing gene therapy protocols for hemophilia A has been achieving sufficient expression from fVIII transgenes in a safe controllable manner. In addition, gene therapy protocols for hemophilia A overlook the immunosensitive patient population. In order to combat these shortcomings, we intend to utilize a non-viral genome editing method that will safely control integration and target a high- expression fVIII transgene (HPFVIII) to a specific location in the genome. By exploiting the repair mechanism of homologous recombination, the CRISPR-Cas9 system will be utilized to edit the genome of hematopoietic stem and progenitor cells. Two active loci, the 1) RhD locus and the 2) von Willebrand Factor (vWF) locus, will be evaluated, one for each hemophilia A subpopulation (those without neutralizing antibodies and those containing neutralizing antibodies). Since the RhD locus is disrupted in a substantial portion of the general population and found to be phenotypically asymptomatic, this location in the genome is optimal for addition of an exogenous gene. These studies will confirm the utilization of the RhD locus as a safe harbor extending the application of this study beyond treating individuals with hemophilia A without neutralizing antibodies. The vWF locus, on the other hand, is an attractive locus for the integration of HPFVIII for the correction of hemophilia A in immunosensitive patients. This is due to the confinement of vWF to the α granules of platelets. Thus HPFVIII, if regulated by the same regulatory elements as vWF, would be safely sequestered from the immune system in the granules of platelets until physiologically necessary. These studies will confirm that the sequestration of HPFVIII in platelets is feasible for the treatment of hemophilia A patients that produce inhibitors. In this manner, two novel gene editing protocols for the treatment of the entire hemophilia A population will be evaluated.

标题