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Developing gene therapy strategies to treat alpha thalassemia

开发治疗α地中海贫血的基因治疗策略

基本信息

批准号：
10545021
负责人：
Tippi Mackenzie
金额：
$ 71.1万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10545021
关键词：
Address Adult Affect Alleles Binding Biological Assay Birth Blood Transfusion CRISPR screen Caring Cell Differentiation process Cell Transplantation Cells Chronic Chronic Disease Clinic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Compensation Data Disease Dissociation Embryo Engraftment Ensure Erythrocytes Erythroid Erythropoiesis First Pregnancy Trimester Frequencies Gene Deletion Gene Mutation Genes Globin Grant Guide RNA Health Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hemoglobin Hemoglobin H Hemoglobinopathies High Pressure Liquid Chromatography Human Immigration Immunodeficient Mouse In Vitro Initiator Codon Institution International Intrauterine Blood Transfusion Length Lentivirus Vector Mediating Medical Mendelian disorder Morbidity - disease rate Mus Mutate Neurological outcome Nucleic Acid Regulatory Sequences Outcome Oxygen PTPRC gene Patients Pattern Phase I/II Clinical Trial Production Proteins Regimen Registries Safety Scheme Severity of illness Site Specificity Stem cell transplant Testing Toxic effect Transfusion Transgenes Transplantation Work alpha Globin alpha thalassemia major alpha-Thalassemia beta Globin beta Thalassemia derepression design experimental study fetal first-in-human functional restoration gamma Globin gene replacement gene therapy genome editing hematopoietic stem cell differentiation improved in utero in vivo innovation insertion/deletion mutation iron chelation therapy postnatal pre-clinical reconstitution repaired restoration southeast Asian treatment strategy vector zeta Globin

项目摘要

ABSTRACT Alpha-thalassemia is one of the most common monogenic diseases in the world; while the carrier frequency is highest in those with South East Asian heritage, there is an expanding health burden in the US due to immigration patterns. Although the most severe form of disease, α-thalassemia major (ATM, in which all four alpha-globin genes are deleted), was formerly often lethal in utero, numerous patients are now surviving to birth after intrauterine blood transfusions, often with excellent neurologic outcomes. However, these patients have a severe chronic disease that requires monthly transfusions or a stem cell transplantation after birth. Patients with a three-gene mutation (such as those with Hemoglobin H-Constant Spring, HbH-CS) can also have severe disease requiring chronic transfusions. While several gene therapy treatments have been developed for patients with β-thalassemia, there are no such therapies for patients with the most severe forms of α-thalassemia, indicating a major unmet medical need. Due to the similarity to β-thalassemia—lack of functional hemoglobin tetramers and formation of toxic globin aggregates in absence of the corresponding binding partner—we believe we can adapt gene therapy strategies that have successfully corrected β-thalassemia in the clinic into analogous approaches for correction of α-thalassemia. These strategies include: 1) CRISPR/AAV- mediated genome editing to replace a copy of β-globin with an α-globin transgene (Aim 1, conducted by Drs. Matthew Porteus and Kyle Cromer at Stanford); 2) Lentiviral delivery of an α-globin cassette with erythroid-specific expression (Aim 2, conducted by Dr. Donald Kohn at UCLA); and 3) CRISPR- mediated de-repression of ζ-globin, the embryonic precursor to α-globin (Aim 3, conducted by Drs. Tippi MacKenzie and Bruce Conklin at UCSF). Our multi-institutional team has been actively collaborating to develop these strategies and the preliminary data presented in this grant. All three independent strategies will be developed in vitro and assessed based on their ability to normalize the globin chain imbalance and restore functional hemoglobin tetramers to α-thalassemia-derived HSCs (obtained from patients with ATM and HbH-CS cared for at UCSF). Furthermore, primary and secondary mouse transplantation experiments will be performed to ensure that edited HSCs retain their ability to engraft and reconstitute hematopoietic lineages in vivo. The expected outcome of the proposed work is a significant advancement toward a universal cure for α-thalassemia by generating substantial pre-clinical data (for one or more approaches) that may be developed into an IND with the FDA for an innovative first-in-human phase I/II clinical trial for ex vivo correction of this disease.

摘要