UC Davis stem researchers demonstrate safety of gene therapy using adult stem cells

Today, gene therapy using the adult blood-forming cells found in bone marrow (known as hematopoietic stem cells) is normally done in an autologous transplant setting. The therapy involves taking hematopoietic stem cells from a person who needs treatment, genetically modifying the cells — perhaps by adding a missing gene — and then re-inserting the cells back into the same person. This treatment eliminates the complications of graft-versus-host disease or host rejection that can occur in allogeneic transplants (therapy where the cell donor is different from the recipient).

In the current study, 630 immunodeficient mice received mesenchymal stem cells from one human bone marrow donor and hematopoietic stem cells from another. Mesenchymal stem cells are a type of cell found in bone marrow that support the function of hematopoietic stem cells, and can give rise to bone, cartilage, fat, and muscle. Genes were inserted into the hematopoietic stem cells using one of two viral vectors — either a retrovirus or a lentivirus — before they were transplanted into the mice, along with genetically modified mesenchymal stem cells.

Of the mice used in the long-term study, four developed human leukemia. None of those mice, however, were found to have vector DNA present in the malignant cells.

"This is evidence of a natural tendency for human bone marrow stem cells to develop leukemia in long-term studies, not that the leukemia was caused by the genetic modification," Bauer explained. "It's a good statistical control for our method."

Bauer noted that while the current study results are important for use with adult stem cells, they are not applicable to human embryonic stem cells, which have completely different properties.

"Our experiments did not involve human embryonic stem cells, so we have a lot of stringent work to do to ensure that those types of stem cells can be used safely for human clinical trials," said Bauer. "It certainly is possible, and we are working hard to establish safe and effective human embryonic stem cell-based cures for patients as well."

Nolta and Bauer have worked on eighteen cell and gene therapy clinical therapy trials during their 12 years as colleagues, including stem cell gene therapy trials for adenosine deaminase deficiency, also known as the "Bubble Boy Disease," and stem cell gene therapy for HIV, with colleagues from Children's Hospital Los Angeles, who are also co-authors on the current report.