Medical Triumph: Gene Therapy Gives Shot at Normal Life

F. Perry Wilson, MD, MSCE


May 12, 2021

This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I'm Dr F. Perry Wilson of the Yale School of Medicine.

This molecule here is deoxyadenosine.


Your body is producing it right now as a product of the breakdown of nucleic acids in your cells. It is highly toxic to immune cells — so toxic, in fact, that if you couldn't quickly break it down, those cells would die, leaving you exquisitely vulnerable to infection.

Fortunately, the chances are that your DNA codes for a protein called adenosine deaminase (ADA), which breaks deoxyadenosine down into more manageable substances.

But about 1 in 100,000 people are born with mutations in their ADA gene. For most of them, the buildup of deoxyadenosine prevents their immune system from ever developing. The condition is known as ADA–severe combined immunodeficiency, or SCID; untreated, most children born with ADA-SCID will die from infection before the age of 2.

SCID evokes the image of the "bubble boy." This is David Vetter, the child on whom the John Travolta movie was based.


But ADA-SCID does not require living in complete isolation anymore. The standard of care these days is stem cell transplant, ideally from a matched sibling. But even matched transplants require lifelong immunosuppression, and only 20% of children with ADA-SCID find a match. Twice-weekly pegylated-ADA injections are considered a temporizing measure, but they don't seem to lead to as robust immune reconstitution as transplant does, and they can be prohibitively expensive.

But there is another option: gene therapy.

Gene therapy for ADA-SCID started in the mid-'90s but had middling results; the altered cells didn't live long enough in the body to provide much protection.

In 2009, the first report of truly successful gene therapy for ADA-SCID appeared in The New England Journal of Medicine.

The authors reported restoration of ADA levels in 8 out of 10 participants. While this was no doubt a huge advance, a patient treated with this therapy subsequently developed T-cell leukemia, which may have been due to insertional oncogenesis (when the introduced gene gets stuck in the genome in a place that promotes cancer).

Now, a new report, again in The New England Journal, suggests that gene therapy for ADA-SCID is ready for the spotlight.

The paper reports on 50 kids in the US and Europe treated with gene therapy for ADA-SCID. The key advance was the use of a lentiviral vector which, in theory, should be less prone to causing cancer down the road. Of the 50 kids, 48 of them are, for lack of a better term, cured.

Here's how the process works.

First, stem cells are harvested from the bone marrow or peripheral blood.

Outside of the body, they are exposed to a lentivirus vector that contains the ADA gene in RNA form.

The virus has been modified so that it can no longer replicate, but it includes the genetic machinery to change the RNA to its complementary DNA and to integrate that DNA strand into the nuclear DNA of the host cell.

The stem cells, now expressing ADA, are counted, evaluated for sterility and viability, and prepared for reinfusion. Meanwhile, the patient gets busulfan to knock down the number of wild-type stem cells in his or her bone marrow — essentially making room for the modified cells to engraft.


The modified cells are then reinfused, and if all goes well, they take up residence in the bone marrow, start dividing, and give rise to immune cells that can metabolize all that deoxyadenosine.


Two of the 50 kids did not have successful engraftment; both restarted enzyme replacement, and one found a donor for a stem cell transplant.

But I want to focus on the 48 kids with successful engraftment. The average age of kids in this study was just under 1 year old. The average ADA level in their blood before treatment was close to zero. After treatment, it shot up.

Deoxyadenosine (the toxic metabolite) plummeted. Genetic labels attached to the new ADA gene were detected in all sorts of white blood cells: granulocytes, T cells, B cells. The immune system was working again.

The New England Journal of Medicine © 2021.

White cell counts normalized. Immunoglobulin levels normalized. None of the 48 kids required ADA injections again. And they don't require immunosuppressive medications either.

I mean, I know most of us aren't caring for kids with SCID; this study is not going to change my everyday practice. But sometimes you just have to stand back and appreciate how science has allowed us to alleviate human suffering. It's nice to remember how this whole thing we do is supposed to work.

At the time of this writing, after 2-3 years of follow-up, all 50 kids are still alive.

Of course, no therapy is without risk. Fifteen kids had severe infections after gene therapy, which may have been due to the bone marrow conditioning regimen. Other adverse effects included an immune reconstitution syndrome requiring transient steroid use in two kids. Gastrointestinal problems and fever were pretty common too.

But of particular note are the events that didn't occur — at least, not yet. No cancers, no autoimmune diseases, and no emergence of replication-competent lentivirus.

Of course, it's only been a few years since these kids were treated. We don't know if this will last forever or if they will need another course of treatment. These children will be monitored for the rest of their lives.

But it's hard for me to look at this as anything other than a triumph. This therapy is giving these kids something that 20 years ago would have been thought impossible: a chance at a normal life.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale's Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at

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