Genetic engineering of hematopoiesis: current stage of clinical translation and future perspectives.

Luigi Naldini

doi:10.15252/emmm.201809958

Abstract

Here I review the scientific background, current stage of development and future perspectives that I foresee in the field of genetic manipulation of hematopoietic stem cells with a special emphasis on clinical applications.

Highlights

Hematopoietic stem cell gene therapy (HSC GT) is becoming a powerful and versatile strategy to treat a growing number of human diseases
A schematic representation of HSC GT showing the crucial steps of the process and its potential clinical applications: (1) Hematopoietic stem/progenitor cells (HSPC) are harvested from the mobilized peripheral blood or bone marrow of a patient and (2) cultured ex vivo in suitable conditions allowing maintenance or expansion of the rare cells with long-term repopulating potential, while they are subjected to gene transfer or gene editing
The extent of homology-dependent recombination (HDR)-mediated DSB repair still decreases as we move from the most committed to the most primitive HSPC in culture, resulting in hematopoietic grafts of xenotransplant recipients comprising ≤ 20% HDR-edited cells in the long term and showing oligoclonal composition. Whereas these levels of editing may be sufficient to treat some primary immunodeficiencies (PID), such as SCID-X1, in which a relatively small fraction of functional progenitors in the administered cell product nearly completely rescued the T-cell deficiency in mouse models and in early gene therapy trials performed with relatively inefficient c-retroviral vectors (Fischer et al, 2015; Schiroli et al, 2017), they may be limiting in other applications, where more robust correction is needed, of long-term repopulating HSC