Optimizing autologous cell grafts to improve stem cell gene therapy

Abstract

Over the past decade, stem cell gene therapy has achieved unprecedented curative outcomes for several genetic disorders. Despite the unequivocal success, clinical gene therapy still faces challenges. Genetically-engineered hematopoietic stem cells (HSCs) are particularly vulnerable to attenuation of their repopulating capacity once exposed to culture conditions, ultimately leading to low engraftment levels post-transplant. This becomes of particular importance when transduction rates are low or/and competitive transplant conditions are generated by a reduced intensity conditioning in the absence of a selective advantage of the transduced over the unmodified cells. These limitations could partially be overcome by introducing mega-doses of genetically-modified CD34+cells into conditioned patients or by transplanting HSCs with high engrafting and repopulating potential. In the present review, based on the lessons gained from the cord blood transplantation, we summarize the most promising approaches to date of increasing either the numbers of HSCs for transplantation or/and their engraftability, as a platform towards the optimization of engineered stem cell grafts.

Chimerism and gene therapy — Lessons learned from non‐conditioned murine bone marrow transplantation models

“…Although our conclusions are based on animal data and will have to be confirmed by further translational research, the results could represent a plausible starting point for future studies on non‐conditioned BM transplantations for gene therapies in humans. Our data can also complement other attempts aimed at the improvement of stem cell‐based gene therapies, such as the optimization of HSC mobilization schedules, improved engineering of stem cell grafts, ex vivo expansion of transduced cells, priming of stem cells, pharmaceutical enhancement of their engraftment capacity, or even the use of reduced intensity regimens before transplantation, as reviewed recently.…”

“…As HSPCs can be most effectively used as a delivery system for gene therapy, HSPCs carrying an edited or healthy genome have been used for several indications such as SCID, Wiskott‐Aldrich syndrome, X‐linked severe combined immunodeficiency, β‐thalassemia major, adrenoleukodystrophy, and metachromatic leukodystrophy, and the number of other potential indications is rapidly increasing . Although many factors affect the engraftment and further behavior of the gene‐modified hematopoietic/precursor cells, such as the effectiveness of the genome editing techniques and the engraftment capacity of the carrier cells, the level of stable chimerism remains one of the key factors in the success of the therapy . A more accurate method of determining the exact number of cells needed to ensure the correct level of chimerism is therefore needed.…”

“…editing techniques and the engraftment capacity of the carrier cells, the level of stable chimerism remains one of the key factors in the success of the therapy. 6,7 A more accurate method of determining the exact number of cells needed to ensure the correct level of chimerism is therefore needed.…”

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

“…Recent progress has been achieved in the harvesting and expansion of healthy HSPCs [57]. Although this progress is of great value, caution is required when translating these findings into a diseased HSPC setting [58]. Furthermore, cord blood cells (often used as a source of healthy HSPCs) do not have exactly the same biological characteristics as their adult counterparts, and HSPCs derived from children under the age of 10 behave differently in culture [59].…”

Rapid prediction of stem cell mobilization using volume and conductivity data from automated hematology analyzers

“…Hematopoietic stem cell (HSC) transplantation, including autologous transplantation, is a valuable therapeutic approach in the treatment of several diseases, most commonly in hematologic neoplasms, and particularly multiple myeloma, both early in therapy and at relapse . Several sources of HSCs may be used, including marrow harvest, peripheral blood–derived stem cells, and potentially even ex vivo expanded or engineered precursors . While there is significant debate over the optimal source of HSCs and the relevant physiologic differences between them, peripheral blood–derived HSCs collected by apheresis are an important and comparatively less‐invasive approach to stem cell collection.…”