权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Hematopoietic Stem Cell Gene Therapy for Friedreich's ataxia

造血干细胞基因治疗弗里德赖希共济失调

基本信息

批准号：
10413884
负责人：
Stephanie Cherqui
金额：
$ 34.56万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413884
关键词：
15 year old Age Allogenic Applications Grants Ataxia Autologous Biochemical CD34 gene CRISPR/Cas technology Cardiac Cardiomyopathies Cell Therapy Cells Complementary DNA Cystinosis Data Development Disease Engraftment Exhibits Foundations Friedreich Ataxia Future Gene Delivery Gene Expression Genes Genetic Transcription Hematopoietic stem cells Hereditary Disease Histologic Human Infusion procedures Introns Investigational Drugs Lead Lentivirus Vector Life Lysosomes Mediating Microglia Mitochondria Mitochondrial Proteins Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Cells Muscle Weakness Mutate Mutation Nanotubes Nerve Degeneration Neurologic Neurons Onset of illness Pathology Patients Peptide Elongation Factor 1 Phase I/II Clinical Trial Phenotype Physiological Proteins Risk Sensory Stem cell transplant Symptoms Testing Therapeutic Effect Time Tissues Transgenes Transplantation Treatment Efficacy Wheelchairs Work clinical application clinical phenotype clinical translation curative treatments expectation frataxin gene correction gene therapy hematopoietic differentiation high risk in vitro testing in vivo iron metabolism macrophage mortality mouse model novel therapeutics overexpression post-transplant prevent promoter restoration stem cell gene therapy success transplantation therapy treatment strategy

项目摘要

Project Summary Friedreich’s ataxia (FRDA) is a multi-systemic autosomal recessive disorder that is predominantly caused by an homozygous GAA repeat expansion mutation within the first intron of the frataxin (FXN) gene leading to a decrease of its expression. Frataxin is a mitochondrial protein involved in iron metabolism. FRDA is characterized by ataxia, neurodegeneration, muscle weakness, and cardiomyopathy. There is no treatment for this lethal disease. We tested a new therapy for this disease consisting in wildtype (WT) hematopoietic stem and progenitor cell (HSPC) transplantation in the Y8GR mouse model of FRDA. This model expresses exclusively the mutated human FXN transgene, thus mimicking the transcriptional deficiency seen in FRDA patients and the clinical phenotype. The premise for using this strategy came from our previous data on cystinosis, a multi-systemic lysosomal storage disorder, which was rescued by HSPC transplantation via differentiation of the HSPCs into macrophages within tissues and transfer of cystinosin-bearing lysosomes via tunneling nanotubes (TNTs) to the adjacent diseased cells. TNTs can also transfer mitochondria, thus we hypothesized that this strategy could also treat FRDA. This therapy worked quite beyond our expectation in FRDA as the neurologic, muscular and cardiac complications were completely corrected up to 7 months post-transplantation (latest time point tested) after a single infusion of HSPCs in lethally irradiated Y8GR mice. Given the high risk of morbidity and mortality associated with allogeneic HSPC transplantation, our objective is to develop an autologous HSPC gene therapy approach for FRDA. Because overexpression of the frataxin is toxic, we will test two different approaches to ex vivo gene-correct and restore a physiologic expression of the gene in the HSPCs. One strategy will be to introduce in HSPCs the human FXN (hFXN) cDNA under the control of a short form of its endogenous promoter using a lentivirus vector. As most of the patients carry a GAA repeat expansion, the second approach will be to use a CRISPR/Cas9-mediated gene editing approach to remove this mutation in HSPCs. Human and murine FRDA HSPCs will be used. Finally, we will also determine the ability of HSPC transplantation to reverse preexisting complications. This work represents the first autologous gene-corrected HSPC transplantation treatment strategy for FRDA and builds the foundation for a clinical application of this strategy.

项目总结