“I remember asking the doctor if my daughter was going to die,” said Chelsea Oakley, mother of Cora Oakley, a newborn who was diagnosed with ADA-SCID when she was just seven days old, in April 2017. “His response was, ‘I hope not.’ It was the darkest day of my life.”

Cora was the last child to enroll in a clinical trial of a gene therapy for ADA-SCID, or severe combined immunodeficiency due to adenosine deaminase deficiency. After receiving her own corrected cells in September 2017, Cora spent a month in the bone marrow transplant unit close to her family’s home. Observing the other young patients, the Oakleys witnessed what her daughter would have gone through if the experimental gene therapy hadn’t been an option.

“I saw young bone marrow transplant patients who developed graft-versus-host disease and others who had to take all these antirejection medications and still had issues,” recalled Chelsea Oakley. “I just thought no one should have to suffer like this. And then here’s my daughter who had this life-changing treatment that felt like a miracle. It still shocks me all the time how unbelievably fortunate we are.”

The Oakley’s experience dramatizes how autologous gene therapy can be doubly advantageous. Besides curing dreadful diseases, gene therapy can help patients avoid the complications of alternative treatments such as transplants of donor-provided stem cells (which carry risks such as graft-versus-host disease and side effects from chemotherapy) and enzyme replacement therapy (which does not fully reconstitute immune function and must be taken for life, usually once or twice weekly).

Cora Oakley numbers among 50 children who were recently evaluated for their response to an experimental gene therapy that was developed by a team of researchers from UCLA and Great Ormond Street Hospital (GOSH) in London. According to an article (“Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency”) that appeared May 11 in the New England Journal of Medicine, 48 of the 50 children retain replenished immune system function two to three years after receiving treatment.

The article’s authors, led by UCLA’s Donald Kohn, MD, and GOSH’s Claire Booth, MB, BS, PhD, detailed the two- and three-year outcomes for children treated with the investigational lentiviral gene therapy in clinical trials at GOSH, UCLA Mattel Children’s Hospital, and the National Institutes of Health between 2012 and 2017.

“Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study,” the article’s authors wrote. “Patients had sustained metabolic detoxification and normalization of ADA activity levels.

“Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade.”

The gene therapy that was evaluated in the study begins with the collection of some of the child’s blood-forming stem cells, which have the potential to create all types of blood and immune cells. Next, by means of an approach developed by the research team, a new copy of the ADA gene is delivered into the stem cells by a modified lentivirus, or viral vector. The corrected cells are then returned to the child’s body, where they are intended to produce a continual supply of healthy immune cells capable of fighting infection.

Prior to teaming up, both Booth and Kohn worked separately for years on successful gene therapies for ADA-SCID that used viral vectors made from retroviruses. Retroviral vectors, however, can only enter cells’ nuclei to deliver genes while the cells are dividing, limiting the number of cells receiving the genetic payload and, thereby, the potential efficacy of the treatment.

Additionally, while neither Kohn nor Booth observed serious complications in their ADA-SCID trials, other earlier studies testing retroviral vector-based gene therapies did report some serious side effects, including leukemia, in some patients.

In 2008, Booth and Kohn began collaborating with professors Bobby Gaspar, MB, BS, and Adrian Thrasher, MB, BS, of University College London to develop an improved viral vector using a different kind of virus, called a lentivirus. Viruses of this kind can enter nondividing cells’ nuclei and, when used as vectors, have the potential to make gene therapies safer and more effective. ADA-SCID patients began receiving the new gene therapy at GOSH in 2012; the following year, the experimental treatment was offered at UCLA and the NIH.

“More than 200 patients with various genetic conditions across the world have now been treated with experimental lentiviral gene therapies, and applying gene therapy to ADA-SCID is another significant scientific advance,” said Thrasher, a senior author of the study who is also a professor of pediatric immunology at GOSH.

Ten of the children in the UCLA study were treated using a frozen preparation of corrected stem cells. These children experienced similar outcomes to the children treated with cells that were not frozen. The freezing approach may allow children with ADA-SCID to have their stem cells collected locally, then have them transported and processed at a manufacturing facility elsewhere and shipped back to a specialized hospital near them, removing the need for patients and their families to travel long distances to specialist centers.

Cora Oakley, who received the gene therapy in September 2017, with her mother, Chelsea. [Chelsea Oakley]
One of the children who received a frozen preparation of cells was Cora Oakley. Now a healthy and exuberant 4-year-old, Cora is described by her mom as a “rough and tumble, outdoors kind of kid” who loves all animals and is incredibly social. “I’ll never forget what it felt like when we didn’t know if she’d ever be able to do any of these things,” Oakley said.

ADA-SCID, which is estimated to occur in approximately 1 in 200,000 to 1,000,000 newborns worldwide, is caused by mutations in the ADA gene that impair the activity of the adenosine deaminase enzyme needed for healthy immune system function. This impairment leaves children with the condition highly susceptible to severe infections. If untreated, the disease is fatal, usually within the first two years of life.

If the ADA-SCID gene therapy is approved, it could become standard for ADA-SCID and many other genetic conditions, said Booth, who added that it could remove “the need to find a matched donor for a bone marrow transplant and the toxic side effects often associated with that treatment.”

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