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Improving the Efficiency of Clinical Gene Therapy

Jul 23, 2018 10:09:00 AM / by Nancy Andon, MSc

Mobilized peripheral blood is collected from human donors-711165-editedAn independent study [1] cites using HemaCare-sourced human cord blood, bone marrow, and mobilized peripheral blood as the starting material in a new strategy for more efficient genetic modification of human stem cells.

The study is based at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Researchers there have been looking into ways to make gene transduction, which is used to introduce an edited copy of a human gene into stem cells, more efficient. The new strategy is part of their goal to improve the potency and long-term engraftment of stem cells used for gene therapy in the clinic.

Gene therapy is a term most often used to describe the effort to cure a disease or condition by replacing a defective inherited gene. These mutated genes can lead to serious diseases such as cystic fibrosis, sickle cell, or hemophilia. Gene therapy can also refer to genetic modification of hematopoietic stem and progenitor cells to re-establish healthy immune function in patients with cancer of the blood or bone marrow.

The primary challenges to the effectiveness of gene therapy are low transduction rates, where the “corrected” gene isn’t taken up by the cell, low expansion rates, where the modified stem cells don’t engraft well enough to start making new immune cells, and low persistence of the modified cells, where the therapeutic effect doesn’t last long enough to do the patient much good. Scientists have been working steadily to improve these factors over the years, and the Milan group’s research is a big step forward.

The authors involved in this study obtained human stem and progenitor cells for their research from HemaCare, along with other commercial suppliers. They decided to incorporate several process improvements at once, in what they hoped would result in an overall more efficient gene therapy strategy. Early on in their experiments, they noted that only a small fraction (10%) of the isolated CD34+ stem cell population correlated with long-term engraftment. [2] After experimenting with various cell sorting strategies, they were able to isolate specific stem cell subpopulations that capture 90% of long-term engraftment activity. In addition to this, the group used prostaglandin E2 stimulation to achieve near complete gene transduction efficiencies with shorter-than-average culture times. Longer culture times have been associated with loss of progenitor cell function. Finally, the scientists made use of another stem cell-stimulating factor, known as UM171, to enhance expansion of their highly purified, genetically modified cells.

The last hurdle in this study was to test whether their gene therapy strategy would work in vivo. The authors used a mouse model to demonstrate successful transplantation, expansion, and long-term engraftment of their transduced, purified stem cells. They concluded that the new gene therapy strategy has promising potential to improve efficacy and efficiency of gene editing techniques in future clinical studies.   



  1. Zonari E., et al. Efficient Ex Vivo Engineering and Expansion of Highly Purified Human Hematopoietic Stem and Progenitor Cell Populations for Gene Therapy. Stem Cell Reports. 8 (4); 977-990. 11 April 2017.
  2. Biasco, L., et al. In vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases. Cell Stem Cell 19, 107–119. 2015.

Topics: Gene Therapy, Bone Marrow, Cord Blood, Stem Cells

Nancy Andon, MSc

Written by Nancy Andon, MSc

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