One-off gene therapy for rare immune disease still effective 10 years later
A long-term follow-up study tracking a group of children who received experimental gene therapy as part of an early-stage clinical trial is reporting the treatment is safe and effective up to 10 years later. The research offers rare insight into the long-lasting effects of a yet-to-be-approved gene therapy.
Back in 2009 a Phase 2 clinical trial recruited 10 children with a rare immune disease known as severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID). The condition is informally known as the "bubble-boy" disease, and it involves mutations in the ADA gene resulting in a dysfunctional immune system.
The experimental gene therapy involved extracting stem cells from a child’s bone marrow and using a modified retrovirus to deliver healthy copies of the ADA gene to the stem cells. The corrected cells are then transplanted back into the child, and if all works as it should, the cells begin producing functional immune cells essentially curing the genetic disease.
In the first few years of the Phase 2 trial, nine out of 10 children responded extraordinarily well. The only non-responsive participant in the trial was also the oldest, at 15 years of age. It was hypothesized the gene therapy may be most effective when administered at an early age.
For the nine successful participants, the single dose gene therapy was impressively effective. And now, nearly 11 years later, the researchers are reporting on the long-term effects of the treatment.
“What we saw in the first few years was that this therapy worked, and now we’re able to say that it not only works, but it works for more than 10 years,” says Donald Kohn, senior author of the new study. “We hope someday we’ll be able to say that these results last for 80 years.”
All nine subjects show no adverse effects from the therapy a decade later, with functioning immune systems offering crucial insights into the long-lasting efficacy of a still-experimental gene therapy. Interestingly, the researchers do note significant differences in immune function were detected between the nine subjects.
Those who received higher initial doses of the therapy at a younger age showed the best immune system functions 10 years down the line. Kohn speculates this could indicate initial levels of gene-corrected stem cells may influence long-lasting efficacy.
“What these results tell us is that there’s a formula for optimal success for ADA-SCID, and it involves correcting more than 5 to 10% of each patient’s blood-forming stem cells,” says Kohn. “The relationship between the levels of gene-corrected cells and immune system function has never been shown so clearly before.”
The new follow-up study does point to one ongoing safety concern flagged by other gene therapy trials. The researchers detected some perturbations in genes relating to cell growth. In other gene therapy trials these signs have led to cells turning cancerous, causing diseases such as leukemia. However, no signs of cancer were found in any of the nine subjects in this particular trial.
This specific safety concern is suspected to be related to the virus used as the delivery mechanism for the corrected gene. This older trial utilized retroviruses to deliver its payload, but these viruses can only slip into a cell’s nuclei when it's dividing. This can limit its efficacy and potentially play a role in disrupting other genes.
Kohn and colleagues have since shifted to using modified lentiviruses as the viral vector for gene therapies. These viruses can enter the nuclei of non-dividing cells meaning they should be safer and more effective in the context of gene therapy.
Earlier this year Kohn and his team published results from a Phase 1/2 trial testing their newer ADA-SCID gene therapy with a lentivirus vector. At the three-year follow-up the study reported 48 out of 50 children treated with the gene therapy were still essentially cured of the disease.
So although the specific form of gene therapy being tracked in this new study is unlikely to ever reach clinical use, the findings offer valuable clues to the long-term efficacy of these kinds of treatments. Kohn points out these long-lasting findings offer hope that one-off gene therapies can deliver enduring life-long results.
“Knowing that a gene therapy can have this lasting effect in ADA-SCID for more than a decade is important for our path forward as we develop new gene therapies for this and other diseases,” says Kohn.
The new study was published in the journal Blood.