Internship for Students of Laurea Magistrale in Biotecnologie / Scienze Farmaceutiche / Biologia
Genome-wide definition of regulatory elements in human primary erythroid cells for the development of a stem
cell-based therapy of β-hemoglobinopathies.
Sickle cell disease (SCD) and β-thalassemias are genetic diseases caused by mutations in the gene coding for
the adult hemoglobin β-chain. They represent the most common monogenic disorders worldwide, affecting thousands
of newborn annually. β-globin disorders may lead to a severe clinical phenotype characterized by anemia, pain crises,
and organ damage. So far, the only curative treatment is represented by bone marrow transplantation from a compatible
donor, but it is available to less than 30% of the patients. Therapies that are in the experimental stages include gene
therapy and pharmacological intervention. In the latter approach, efforts are underway to identify compounds that raise
the expression of the fetal -globin genes. The rational for this treatment is based on the long-standing observation that
patients with linked mutations that trigger elevated -globin expression, which are normally expressed only during fetal
life, experience a more benign clinical course of the disease. Unfortunately, both gene therapy and pharmacological
therapies have potential drawbacks, such as the genotoxic risk and the systemic toxicity, respectively.
The aim of the proposed projects is to provide the knowledge for developing safe therapies to SCD and βthalassemias based on gene editing approaches aimed to increase -globin expression. The mechanisms and the
regulatory elements that control the switch from fetal to adult globin gene expression will be studied at molecular level.
Studies focused on the molecular mechanisms underlying the β-to--globin switching as well as on the evaluation
of the efficacy and safety of these therapeutic approaches will be proposed during the internship. The student
will apply novel molecular techniques (e.g. genome-wide analyses and CRISPR/Cas9 technology) by using
innovative cellular models (e.g. human iPSCs).
IMAGINE is a recognized institute in Paris (http://www.institutimagine.org/en/) that ensures high quality
research in terms of multidisciplinary training and publication rate. This attractive and competitive international
scientific environment offers a strong expertise in both pediatric and adult genetic disorders and access of all core
facilities and resources required for the project (P2 and P3 laboratories, mouse facility and genomic, bioinformatic, flow
cytometry and cell imaging platforms). Dr. A. Miccio, supervisor of the project, is an international recognized expert in
hematopoiesis, epigenetics and regulation of gene expression in erythropoiesis, hemoglobinopathies, LV and nucleases
technologies and genotoxicity assessment. Additionally, she already established strong international collaborations with
outstanding experts in disciplines relevant for the projects.
We are looking for highly motivated, enthusiastic students of the second year of the Laurea Magistrale
in Biotecnologie / Scienze Farmaceutiche / Biologia with at least 2-3 months of bench lab experience and a good
knowledge of English for a 9-12 months internship.
Publications:
MICCIO A In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of betathalassemia Proc Natl Acad Sci U S A 2008 105(30):10547-52
MICCIO A NuRD mediates activating and repressive functions of GATA-1 and FOG-1 during blood
development EMBO J 2010 29(2):442-56
GREGORY GD FOG1 requires NuRD to promote hematopoiesis and maintain lineage fidelity within the
Blood 2010 115(11):2156-66
MICCIO A The role of the GATA-1/FOG-1/NuRD pathway in the expression of human beta-like globin genes Mol
Cell Biol 2010 30 (14) :3460-70
MICCIO A The GATA1-HS2 Enhancer Allows Persistent and Position-Independent Expression of a beta-globin
Transgene PLoS One 2011 6(12):e27955
E-mail contact for information request and CV submission: annarita.miccio@institutimagine.org
Annarita Miccio
Laboratory of Chromatin and gene regulation during development
IMAGINE institute - INSERM U1163
24, Boulevard de Montparnasse
75015, Paris (France)