Evangelina Vaccaro received Dr. Kohn’s treatment for bubble baby disease in 2012.
Evangelina Vaccaro received Dr. Kohn’s treatment for bubble baby disease in 2012.

New research by Dr. Donald Kohn of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA could make blood stem cell gene therapy methods safer and more effective. For several decades, Kohn has developed novel approaches for genetic blood diseases and his clinical trials for adenosine deaminase-deficient severe combined immunodeficiency, an immune disorder also known as ADA-SCID or bubble baby disease, have cured 30 out of 30 babies over the past eight years.

The research, published in the journal Blood on March 28, examined the genetic profiles of 15 ADA-SCID clinical trial participants. While all 15 patients showed dramatically improved immune system function and no adverse effects after three to nine years of follow-up, Kohn’s study highlights some of the challenges associated with gene therapy and points to improved methods to overcome those challenges.

What is ADA-SCID (bubble baby disease)?
ADA-SCID is a life-threatening condition caused by a genetic mutation that results in lack of the adenosine deaminase enzyme, which is essential to the immune system’s ability to fight off infection. Children with the disease lack almost all immune defenses. If untreated, ADA-SCID is often fatal within two years.

How does Kohn’s ADA-SCID therapy work?
Kohn’s life-saving ADA-SCID gene therapy method uses each child’s own cells to create an immune system where one did not exist before. The therapy uses blood-forming stem cells, which have two important properties: the cells make exact copies, or clones, of themselves and they produce all of the cells that make up the blood system. The treatment process involves removing blood-forming stem cells from each patient’s bone marrow and correcting the genetic mutation through insertion of the gene responsible for making the adenosine deaminase enzyme. The corrected blood-forming stem cells are then infused back into the patient, where they produce a continual supply of healthy immune cells that fight infection.

The research findings
Kohn and his team tested genetic information from 15 patients who participated in his ADA-SCID clinical trials between 2005 to 2012. The team analyzed how much chemotherapy each patient received prior to the treatment, as well as viral vector integration sites and clonal diversity three to nine years after treatment.

The team found that patients who had the highest clonal diversity went on to develop the best immune system function. This is because the immune system needs diverse immune cell populations to respond to the wide array of existing viruses, bacteria, and other microorganisms in the environment that can cause disease. The team also observed that the gene therapy yielded the best outcomes in the youngest patients, who tend to have more blood-forming stem cells in their bone marrow.

Additionally, the analysis revealed the optimal level of chemotherapy and found that clonal diversity can be improved by increasing the amount of chemotherapy patients receive prior to treatment.

Several patients were found to have viral vector integrations next to oncogenes, however these patients’ cells showed stable behavior over multiple years and none of the patients have developed cancer.

This and many other forms of gene therapy rely on modified viruses called viral vectors to insert corrected genes into cells’ genetic code, which is housed in the cell nucleus. Viral vectors are viruses that have been altered so a virus’ ability to enter cell nuclei can be harnessed to deliver disease-correcting genetic information without the virus causing a disease. Several factors impact blood stem cell gene therapy safety and effectiveness.

One of the critical factors impacting stem cell gene therapy is the integration site, which is the unique and random site where the viral vector lands in the blood stem cells’ genetic code. Sometimes viral vectors can land next to an oncogene, which is a gene that inadvertently activates cell growth. If this happens, that cell can begin to multiply uncontrollably and lead to cancer.

Another important factor is clonal diversity, which relates to how many blood stem cells contain the corrected genetic information at different integration sites. A high number of blood stem cell clones with a large amount of viral vector integration sites means greater clonal diversity. Treatment with chemotherapy can significantly improve clonal diversity; chemotherapy is often used before gene therapy in order to lower existing cell populations in bone marrow to make room for the transplanted corrected blood stem cells.

The viral vector most commonly used in Kohn’s early ADA-SCID clinical trials is called a retroviral vector. One limitation of the retroviral vector is that it can only enter blood stem cells’ nuclei when the cells are dividing, thus reducing clonal diversity.

More recently, researchers have begun to use other viral vectors that provide better clonal diversity and increased safety. One possible solution, known as a lentiviral vector, brings two major benefits. It can be programmed to self-inactivate after reaching its destination; if the lentiviral vector lands next to an oncogene, it will not be able to cause uncontrolled cell growth. Also, a lentiviral vector can enter a cell’s nucleus even when the cell is not dividing, which increases clonal diversity. Kohn’s current clinical trial for ADA-SCID utilizes a lentiviral vector.

The research was supported by the Saban Research Institute of Children’s Hospital Los Angeles, the Doris Duke Charitable Foundation (2000-654), the U.S. Food and Drug Administration (1 RO1 FD003005). the Clinical Gene Therapy Core Laboratory of the Children’s Hospital Los Angeles/University of Southern California General Clinical Research Center (MO1 RR0043), the National Human Genome Research Institute, the National Institute of Diabetes and Digestive Kidney Diseases, the National Cancer Institute, the National Institutes of Health, the Ruth L. Kirschstein National Research Service Award (GM007185) and the UCLA Broad Stem Cell Research Center. 

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