title: Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia.
abstract: Aplastic anemia is a fatal bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia. The disease can be hereditary or acquired and develops at any stage of life. A subgroup of the inherited form is caused by replicative impairment of hematopoietic stem and progenitor cells due to very short telomeres as a result of mutations in telomerase and other telomere components. Abnormal telomere shortening is also described in cases of acquired aplastic anemia, most likely secondary to increased turnover of bone marrow stem and progenitor cells. Here, we test the therapeutic efficacy of telomerase activation by using adeno-associated virus (AAV)9 gene therapy vectors carrying the telomerase Tert gene in 2 independent mouse models of aplastic anemia due to short telomeres (Trf1- and Tert-deficient mice). We find that a high dose of AAV9-Tert targets the bone marrow compartment, including hematopoietic stem cells. AAV9-Tert treatment after telomere attrition in bone marrow cells rescues aplastic anemia and mouse survival compared with mice treated with the empty vector. Improved survival is associated with a significant increase in telomere length in peripheral blood and bone marrow cells, as well as improved blood counts. These findings indicate that telomerase gene therapy represents a novel therapeutic strategy to treat aplastic anemia provoked or associated with short telomeres.
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program and.
authors.forename: Christian
authors.initials: C
authors.lastname: Bär
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program and.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Povedano
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program and.
authors.forename: Rosa
authors.initials: R
authors.lastname: Serrano
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Centre, Madrid, Spain;
authors.forename: Carlos
authors.initials: C
authors.lastname: Benitez-Buelga
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program and.
authors.forename: Miriam
authors.initials: M
authors.lastname: Popkes
authors.affiliation: Roche Pharma Research and Early Development, Neuroscience, Ophthalmology, and Rare Disease, Roche Innovation Center and.
authors.forename: Ivan
authors.initials: I
authors.lastname: Formentini
authors.affiliation: Roche Extending the Innovation Network Academia Partnering Program, F. Hoffmann-La Roche, Basel, Switzerland; and.
authors.forename: Maria
authors.initials: M
authors.lastname: Bobadilla
authors.affiliation: Centre of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program and.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
mesh_terms: D000741:Anemia, Aplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000229:Dependovirus; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D059505:Telomere Homeostasis; D014161:Transduction, Genetic
chemical_list: D019098:Telomerase; C509187:Tert protein, mouse