Gene Therapy with Hematopoietic Stem Cells: The Diseased Bone Marrow's Point of View

Abstract

When considering inherited diseases that can be treated by gene transfer into hematopoietic stem cells (HSCs), there are only two in which the HSC and progenitor cell distribution inside the bone marrow and its microenvironment are exactly the same as in a healthy subject: metachromatic leukodystrophy (MLD) and adrenoleukodystrophy (ALD). In all other settings [X-linked severe combined immunodeficiency (X-SCID), adenosine deaminase deficiency, Wiskott-Aldrich syndrome, and b-hemoglobinopathies], the bone marrow content of the different stem and precursor cells and the cells' relationship with the stroma have very specific characteristics. These peculiarities can influence the cells' harvesting and behavior in culture, and the postgraft uptake and further behavior of the gene-modified hematopoietic/precursor cells. In the present mini-review, we shall briefly summarize these characteristics and outline the possible consequences and challenges.

Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion

“…It is generally acknowledged that 2 to 3×10 6 CD34 + hematopoietic stem and progenitor cells (HSPC)/kg are required for a successful outcome in autologous HSCT. 5 Considering the typical proportion of HSPC that can be corrected in gene therapy clinical trials (~50% of CD34 + HSPC) and an average recovery of 70% of CD34 + cells post-selection, a minimum harvest of ~6×10 6 CD34 + cells/kg would be required. For reasons that have not been completely elucidated, as for thalassemic patients, 6 – 7 the recovery of HSPC from SCD patients’ BM is peculiarly low (M. Cavazzana, unpublished data ).…”

Bone Marrow-Derived Mesenchymal Stromal Cells: A Novel Target to Optimize Hematopoietic Stem Cell Transplantation Protocols in Hematological Malignancies and Rare Genetic Disorders

“…In this sense, profound knowledge of BM stroma biology is fundamental for the optimization of transplantation strategies, especially in the context of HSC-GT, where the relationship between HSPCs and the stroma may influence harvest and behavior in culture, as well as HSC engraftment kinetics after gene modification. Indeed, the functionality of HSPCs could be affected by the diseased microenvironment, and, on the other side, the diseased niche could have a reduced capacity to sustain the engraftment of gene-corrected HSPCs [160][161][162][163].…”

Thérapie génique : beaucoup plus de questions que de réponses

“…La conséquence de cette dysérythropoïèse est l'accumulation de progéniteurs érythroïdes, de cinq à six fois plus élevée que chez un sujet normal, expliquant les échecs initiaux d'obtention d'un nombre de cellules souches suffisant chez ces patients. Le défi de ces prochaines années sera donc de trouver comment, face à l'altération de la composition médullaire propre à chaque maladie, nous pouvons obtenir un nombre de CSH suffisant pour les utiliser à des fins de thérapie génique [3]. Enfin, il devient urgent de simplifier toute la chaîne opé-ratoire.…”