Rare Disease Report

EMA Recommends ADA-SCID Gene Transfer: Blast from the Past

APRIL 11, 2016
Ricki Lewis, PhD
When the European Medicine Agency’s Committee for Medicinal Products for Human Use on April 1 recommended marketing approval of gene transfer to treat adenosine-deaminase-deficient severe combined immunodeficiency (ADA-SCID), the media so widely called it “bubble boy disease” that I wondered whether the story of 4-year-old Ashanthi DeSilva has been lost to history.
Ashi had this gene therapy 26 years ago.
Her experience is testament to the plodding pace of biomedical research and the many decisions and revisions necessary to shepherd a gene transfer experiment into a gene therapy.

ADA Deficient SCID is NOT Bubble Boy Disease

The actual bubble boy, David Vetter, had SCID-X1 and lived his short sad life in a bubble. John Travolta famously depicted him in a TV film “The Boy in the Plastic Bubble” in 1976 and Jerry Seinfeld’s ensemble ridiculed him in 1992. But the diseases shouldn’t be lumped together -- they cripple both arms of the immune system (T and B cells), but in very different ways. ADA-SCID, an enzyme deficiency, is a metabolic disorder with more widespread manifestations than SCID-X1, which results from a mutation in interleukin 2 receptor subunit gamma (IL2RG). Gene therapies for both have been in development for more than two decades. The eight different types of SCID collectively affect only one in 100,000 newborns.
While we await the second gene therapy approval in the EU – first was Glybera for lipoprotein lipase deficiency, in late 2012 – below are highlights of Ashi’s story from my book, The Forever Fix: Gene Therapy and the Boy Who Saved It. Ashi’s story not only launched gene therapy into clinical trials, but had at its center Dr. William French Anderson, who has been in legal difficulties for some time. He helped me with my book, and I’ve told some of his story here.

Ashi’s Story

“The very first gene therapy for an inherited disease happened on September 4, 1990. On that afternoon, four-year-old Ashanthi DeSilva received an infusion of her own T cells, bolstered with working copies of a gene that her failing immune system desperately needed.
Ashi had her first infection at just two days of age. By the time she was walking, she was constantly hacking and dripping with coughs and colds, and just toddling would make her as winded as an elderly chain smoker, recalls her father Raj. Doctors at first offered the common explanations, the horses: asthma, allergy, bronchitis. But standard treatments didn’t work, and Ashi was still ill nearly all the time. Raj’s brother, an immunologist, advised taking a closer look at her immune system, and that led to her diagnosis, just past her second birthday. Lack of the enzyme adenosine deaminase stopped a key biochemical reaction in a way that caused the buildup of a toxin poisoning her T cells, the white blood cells that serve as linchpins of the immune response.
Shortly after her diagnosis, Ashi started a new enzyme replacement therapy that worked well for two years. As her T cell count approached normal, she gained weight and had longer healthy periods. But gradually her T cell count fell, and infections returned. Then the little girl was selected to receive gene therapy at the National Institutes of Health in Bethesda, Maryland. In case it didn’t work, though, her doctors continued the enzyme replacement therapy http://www.adagen.com/enzyme.html. But at $250,000 per patient per year, it is costly and continual.
It took four years from initial submission of the gene transfer protocol to NIH’s Recombinant DNA Advisory Committee (RAC) until Ashi’s treatment, due to politics, priorities, and personalities. Part of the reason for the RAC’s reticence was the sheer strangeness of gene therapy, and the fact that the patient would be a child. Finally, piggybacking the experiment onto a similar protocol being used to treat melanoma helped. Rather than a detour, the foray into cancer was a brilliant way to make the RAC pay attention to a rare disease.
At the RAC meeting on June 1, 1990, when ADA deficiency came up again, the committee asked the researchers about who should be treated. Using the sickest patients would give the clearest results, but was it ethical to deprive them of enzyme replacement therapy to do so? A compromise was to treat very sick kids, but also give them ADA. A friend of one of the researchers referred two of his patients from his practice in Ohio – 4-year-old Ashi and 8-year-old Cynthia. They became the first patients to receive gene therapy.
The RAC advised FDA to approve the proposal. Because the buzz was that another rejection was looming, some of the key journalists following the story didn’t bother to attend the final RAC meeting, nor did anyone from the public. Even though by summer’s end the FDA still hadn’t given a thumb’s up, the researchers started taking Ashi’s white blood cells anyway and adding working ADA genes to them. They wanted to have something to infuse into their first patient once the approval came.
The NIH was getting ready too. On September 3, anticipating imminent FDA approval for the trial, the agency held a press conference to announce what would happen the next day. This time the media paid attention. Jeremy Rifkin, president of the Foundation on Economic Trends http://www.foet.org/, who was making a career of objecting to biotechnology, showed up waving notice of a lawsuit filed because the final RAC decision had come when no one from the public was present.
That night, final FDA approval for the trial still hadn’t happened. Dr. William French Anderson barely slept, heading to the NIH clinical center at 5:30 the next morning. At 8:55, the two agencies finally stopped bickering and the FDA gave their okay. Anderson waited with Ashi in the pediatric ICU. He took more blood, and then, with Ashi’s hometown doctor, they watched Dumbo cartoons. At 12:52 PM, Ken Culver brought in the “soup” – a pint of murky fluid containing about ten billion of Ashi’s corrected white blood cells – and attached the bag to her intravenous line. The infusion took 28 minutes.
Ashi received eleven treatments in all, one to two months apart, plus enzyme every week. She had no side effects, and started improving after a few infusions. At the six-month mark, Ashi, her parents, and her two sisters all came down with the flu, and she was the first to recover. That, her mother said, was when they began to look at their daughter as normal.”

Retooling the Protocol

Ashi continued to resist infection and gradually, corrected T cells appeared in her blood. And stayed. But she and Cynthia were a very small sample size with no controls, and also received the enzyme. Some researchers still question whether that first experiment had, in fact, shown efficacy. And so clinical trials continued, as they do, with changes to the protocol that have contributed to the current success:
  • Much younger patients
  • Minimal or no enzyme given
  • Targeting CD34+ cells from bone marrow and umbilical cord blood, rather than mature T cells
  • Treating with a chemotherapy drug to make more room in the bone marrow
  • Altering gamma retroviruses so that they “self-inactivate” and not insert into oncogenes (as they did for the true bubble boy disease), or using lentivirus
The ADA-SCID gene therapy that the EMA has recommended was developed at the San Raffaele Telethon Institute for Gene Therapy, and GlaxoSmithKline will market it as Strimvelis. My sources tell me that the first approval in the US will happen in 2017, possibly late 2016, for a different type of disease, actually the one that is the subject of my book. (And neither GSK nor the EMA call ADA-SCID “bubble boy disease.”)
Whenever and however that first gene therapy approval happens in the U.S., I hope that the media will avoid the word “breakthrough,” for a quarter-century-plus is not that; describe the correct condition; and respect the long history of this biotechnology and the many people who made it possible.

images courtesy of genome.gov

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