Using novel gene therapy to cure infants born with severe combined immunodeficiency

Out of every 60,000 births, a baby arrives to face the world without a fully functioning immune system leaving them unequipped to fight even the most common infections. Children with this rare life-threatening genetic condition, known as severe combined immunodeficiency (SCID), have the best chance at a healthy future if they undergo a stem cell transplant before they are 3 ½ months old.

Seattle Children's recently opened a clinical trial that is seeking a potentially safer, less aggressive and equally effective path to a cure by using a novel gene therapy to fix the faulty gene that causes the most common type of SCID.

On the Pulse met with the trial's principal investigator, Dr. Aleksandra Petrovic, a pediatric transplant specialist and researcher at Seattle Children's Research Institute's Center for Immunity and Immunotherapies, to learn more about the experimental therapy available through this trial.

Q: What hope does this trial offer to a baby born with SCID?

A: SCID refers to a group of inherited disorders where many genetic abnormalities hinder the development of critical components of the immune system in one way or another. Without treatment, children with SCID will not live past 2 years old. Those fortunate enough to have a sibling match – about 25% of patients – can undergo a bone marrow transplant, with a high rate of success. Otherwise, transplant from an unrelated donor or a parent is the next best treatment option, but provides in some cases only partial correction of the deficiency.

This trial offers a new way to treat one type of SCID called X-linked SCID in newborns with no sibling match. X-linked SCID, or XSCID, affects boys and is the one we see most often. Our hope is that the gene therapy will produce a more robust immune system without the complications associated with transplant in these babies.

Q: How does the gene therapy work?

A: The gene therapy in this trial, which was developed and first tested for safety by St. Jude Children's Research Hospital, manipulates a patient's stem cells by inserting a normal copy of the defective gene into the cell's genome. This gene replacement process is completed in a lab using a non-disease causing form of a virus – a viral vector – to carry the new genetic information into the cells. The modified cells are then infused into the patient facilitating the recovery of the immune system.

For our newborn patients and families, this means they will first come in for a bone marrow harvest to obtain the stem cells needed. These cells will be transported to a cell manufacturing lab where DNA containing the normal gene will be transferred into the patient's cells. Two weeks later, once the new cells are in hand, the baby will receive low dose chemotherapy before having their corrected cells infused.

Q: Why is the chemotherapy needed before the infusion of the cells?

A: This is the first trial to combine gene therapy with low dose chemotherapy in patients with newly diagnosed XSCID, with hope of more complete and durable immune correction. The chemotherapy, in this case a drug called busulfan, helps make space for the new cells to engraft and grow. Our experience with transplant has shown that adding a conditioning chemotherapy results in an immune system that is more complete, meaning we see a wider range of immune cells present and functioning.

Q: When will you know if the therapy has worked?

A: We will monitor the baby closely in the hospital over three to four weeks after the infusion to make sure they remain free of infection and they are able to regain normal blood cell counts. We will also look for any signs that the immune system is being rebuilt with the new cells. The number of T cells, B cells or myeloid cells marked by the vector used to insert the new gene will serve as early indicators of the therapy's success.

Q: What are the anticipated benefits to using gene therapy over transplant in patients with XSCID?

A: We hope to provide a safer alternative to transplant by eliminating the potential for graft-versus-host disease, a complication that can arise during transplantation in which the donor cells attack the recipient's tissues. By using a much lower dose of chemotherapy than what is normally given as part of conditioning prior to transplants, we also seek to reduce the short- and long-term side effects that invasive treatment like transplant may impose on young infants.

We are optimistic that gene therapy can achieve a more robust immune system too. Typically in patients who receive non matched transplants from family members (especially if no chemotherapy is used), you see good T-cell numbers, rarely full B-cell engraftment and no myeloid engraftment. With this therapy, we have the opportunity to have all three infection fighters present and functioning well. This correlates with the longevity of the developing immune system which I believe is an important aspect of this trial.

Q: Is this gene therapy currently available anywhere else?

A: Seattle Children's is one of three sites in the U.S. where this experimental therapy is available today. In the last year, St. Jude and the UCSF Benioff Children's Hospital San Francisco have treated patients with the same protocol we are using here, with promising early results.

Q: Seattle Children's played a significant role in establishing SCID newborn screening in Washington state. How has this measure helped improve the prognosis for children with SCID?

A: With newborn screening for SCID, which began in Washington state in 2014, we are seeing improvement in detecting the disease early. The survival rate for all SCID patients is greater than 90% when we can provide treatment before infections. Even with transplant from a parent or unrelated donor, while it's certainly not a poor prognosis, there are complications down the road if a child is unable to develop a fully functioning immune system or graft-versus-host disease. We hope gene therapy may prove to offer even better results with a fully functional immune system.

Q: How might the results from this trial impact the treatment of other diseases?

A: This trial will set a precedent for subsequent gene therapies that can be replicated based on our results. Clinical trials using gene therapy in other single-gene immune disorders like Wiskott-Aldrich syndrome are already planned to open at Seattle Children's in the near future.

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