Gene Therapy Transforming Lives of Kids with SCID

Severe Combined Immunodeficiency (SCID) used to be a death sentence. Now, gene therapy is helping some of these kids lead normal lives.

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 your DNA codes for a protein called adenosine deaminase 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 conditions is known as ADA-severe combined immunodeficiency or SCID, and, untreated, most children born with ADA-SCID will die from infection before age 2.

SCID evokes the image of the “bubble boy”.

But ADA-SCID does not require living in complete isolation anymore. 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 don’t seem to lead to as robust immune reconstitution as transplant does and can be prohibitively expensive.

But there is another option — gene therapy.

Gene therapy for ADA-SCID started in the mid 90’s, 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.

Absurdly simplified version of ex vivo lentiviral gene transfer

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

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

The virus has been modified so that it can no longer replicate, but includes the genetic machinery to change the RNA to it’s 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 — 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 one year old. The average ADA level in their blood, before treatment, was close to zero. After treatment, it shot up.

All sorts of immune cell types rebounded

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.

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 two to three years of follow-up, all 50 kids are still alive.

Of course, no therapy is without risk. 15 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.

A version of this commentary first appeared on

Writing about medicine, science, statistics, and the abuses thereof. Commentator at Medscape. Associate Professor of Medicine at Yale University.

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