Gene therapy of hemoglobinopathies: progress and future challenges
Autor: | Yasuhiro Ikawa, Janet L. Kwiatkowski, Stefano Rivella, Annarita Miccio, Elisa Magrin, Marina Cavazzana |
---|---|
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Genetic enhancement Genetic Vectors Biology Bioinformatics Viral vector 03 medical and health sciences Hemoglobins 0302 clinical medicine Genome editing Transduction Genetic hemic and lymphatic diseases Fetal hemoglobin Genetics medicine Animals Humans Genetic Predisposition to Disease Molecular Biology Genetics (clinical) Regulation of gene expression Clinical Trials as Topic Hematopoietic Stem Cell Transplantation Hematopoietic stem cell General Medicine Genetic Therapy Bone marrow purging 3. Good health Hemoglobinopathies 030104 developmental biology medicine.anatomical_structure Treatment Outcome Gene Expression Regulation 13. Climate action 030220 oncology & carcinogenesis Mutation Stem cell |
Zdroj: | Human molecular genetics. 28(R1) |
ISSN: | 1460-2083 |
Popis: | Recently, gene therapy clinical trials have been successfully applied to hemoglobinopathies, such as sickle cell disease (SCD) and β-thalassemia. Among the great discoveries that led to the design of genetic approaches to cure these disorders is the discovery of the β-globin locus control region and several associated transcription factors, which determine hemoglobin switching as well as high-level, erythroid-specific expression of genes at the ß-globin locus. Moreover, increasing evidence shows that lentiviral vectors are efficient tools to insert large DNA elements into nondividing hematopoietic stem cells, showing reassuring safe integration profiles. Alternatively, genome editing could restore expression of fetal hemoglobin or target specific mutations to restore expression of the wild-type β-globin gene. The most recent clinical trials for β-thalassemia and SCD are showing promising outcomes: patients were able to discontinue transfusions or had reduced transfusion requirements. However, toxic myeloablation and the high cost of current ex vivo hematopoietic stem cell gene therapy platforms represent a barrier to a widespread application of these approaches. In this review, we summarize these gene therapy strategies and ongoing clinical trials. Finally, we discuss possible strategies to improve outcomes, reduce myeloablative regimens and future challenges to reduce the cost of gene therapy platform. |
Databáze: | OpenAIRE |
Externí odkaz: |