Dyskeratosis congenita is a telomeropathy and an inherited bone marrow failure syndrome whose only curative treatment for the hematological problem is the allogeneic transplantation of hematopoietic stem cells. On the one hand, not all patients find a suitable donor for this complex treatment and, on the other, transplantation involves many complications with high morbidity. Therefore, the search for alternative therapies for this disease constitutes a major health and scientific challenge, with the aim of developing innovative therapies for the treatment of patients with very poor prognosis. In this project, we propose the development of new tools to achieve the efficient correction of hematopoietic stem cells from dyskeratosis congenita patients. Our studies are focused first on the characterization of patient samples and the development of new dyskeratosis congenita models. Then, we also study the phenotypic correction of bone marrow hematopoietic stem and progenitor cells by gene therapy. We investigate two different gene therapy methods: integrative lentiviral transduction with vectors expressing the dyskerin derived peptide GSE4 and targeted gene therapy. This last objective implies the use of CRISPR/Cas9 technology to produce double strand breaks in the targeted region, as well as the generation of a donor DNA template, delivered by serotype 6 adeno-associated vectors (AAV6), with the correct sequence of the target gene. The correction of a sufficient number of hematopoietic stem cells using this combination of CRISPR/Cas9 and AAV6 will allow us to explore the possibility of its future use in clinical trials. The main objective of this project is the development of gene therapy strategies to treat bone marrow failure in X-linked and autosomal dominant variants of dyskeratosis congenita.
Unit Members
Guillermo Güenechea Amurrio. PhD
Diego Llorente Arroyo. PhD Student
M Luz Lozano Vinagre. Technician