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Towards Safe and Effective Hematopoietic Stem Cell Gene Therapy: Targeting Integration to Genomic Safe Harbors and Exploiting Endogenous microRNA to Regulate Transgene Expression

Objective

Hematopoietic stem cell gene therapy has a tremendous potential to treat human disease. Yet, in conjunction with the first successful results in the clinic, severe adverse events linked to the gene transfer protocol were reported. Recently, we provided proof-of-principle of two new powerful strategies to improve the efficacy and safety of gene transfer: 1) regulating transgene expression by exploiting cellular microRNAs; 2) targeting integration at predetermined sites of the genome by forcing homologous recombination with designer Zinc finger nucleases. Here we will investigate the microRNA network regulating hematopoiesis and exploit the new knowledge to develop vectors with stringently controlled expression throughout the hematopoietic lineages. We will develop Zinc finger nuclease-based vectors that insert the transgene with high efficiency and specificity either downstream to its own endogenous promoter or into a safe genomic harbor that allows for robust expression without interference on the neighboring genes. By combining these strategies we will provide radically improved gene transfer platforms. Furthermore, we will exploit these technologies for the generation and genetic correction of induced pluripotent stem cells, providing a potentially unlimited source of patient-derived vector free gene corrected multipotent stem cells for future applications of regenerative medicine. The new gene therapy strategies will be tested in pre-clinical models of leukodystrophies and immunodeficiencies, for which we have extensive experience, and should enter a clinical trial for at least one such disease by the end of the proposed funding period. If successfully validated, the new strategies may eventually broaden the scope of gene therapy in medicine.

Field of science

  • /medical and health sciences/medical biotechnology/cells technologies/stem cells
  • /natural sciences/chemical sciences/inorganic chemistry/inorganic compounds
  • /medical and health sciences/medical biotechnology/genetic engineering/gene therapy
  • /natural sciences/biological sciences/genetics and heredity/genome

Call for proposal

ERC-2009-AdG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

UNIVERSITA VITA-SALUTE SAN RAFFAELE
Address
Via Olgettina 58
20132 Milano
Italy
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 910 800
Principal investigator
Luigi Naldini (Prof.)
Administrative Contact
Maria Rosa Pedrazzi (Dr.)

Beneficiaries (3)

UNIVERSITA VITA-SALUTE SAN RAFFAELE
Italy
EU contribution
€ 910 800
Address
Via Olgettina 58
20132 Milano
Activity type
Higher or Secondary Education Establishments
Principal investigator
Luigi Naldini (Prof.)
Administrative Contact
Maria Rosa Pedrazzi (Dr.)
FONDAZIONE CENTRO SAN RAFFAELE DEL MONTE TABOR

Participation ended

Italy
EU contribution
€ 493 002,13
Address
Via Olgettina 60
20132 Milano
Activity type
Research Organisations
Administrative Contact
Mario Valsecchi (Mr.)
OSPEDALE SAN RAFFAELE SRL
Italy
EU contribution
€ 1 096 197,87
Address
Via Olgettina 60
20132 Milano
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Maria Rosa Pedrazzi (Dr.)