Thanks to a half century of scientific research and effort — an effort that I am proud to have been a part of — there is finally hope for a cure to one of the most devastating genetic disorders affecting young children today. Severe combined immunodeficiency (SCID) is known most widely by its nickname, the ‘bubble baby’ disease. The genetic disorder robs a person of a working immune system and the functional B cells and T cells that normally protect us from disease. Most children born with the disorder — caused by genetic defects — die from opportunistic infection during their first year or two of life, unless they receive regular twice-weekly antibody infusions, which can be both costly and cumbersome to manage.
SCID first became part of America’s collective consciousness in the 1970s thanks to a young boy named David who lived almost his entire life inside a series of sterile plastic bubbles. His life as a “bubble boy” was the subject of endless media fascination, and it earned the disease a place in pop culture through movies and TV. But for whatever entertainment the boy in the plastic bubble brought to the screen, David’s actual life only led to sorrow — he passed away at the age of 12 after a failed bone marrow transplant. Until recently, a stem cell or bone marrow transplant was the only hope of a permanent cure, though these types of procedures came with a great deal of risk.
But now, thanks to the efforts of researchers at the University of California, Los Angeles and Great Osmond Hospital in London, there is renewed hope for a safer cure. In a study published in the New England Journal of Medicine, the researchers show how an experimental form of gene therapy could restore the immune system of those living with SCID. Fifty patients were given the treatment — 30 patients in the United States and 20 in the UK. After 36 months, 90% of the US patients and 100% of the UK patients had fully reconstituted immune systems and were able to discontinue their antibody infusions. The children were essentially returned to normal life, able to play with friends, go to school, and fight off the common colds and normal infections that in the past could have killed them. Among the patients in the trial, there were no complications with the treatment and most adverse events reported were mild or moderate.
The experimental gene therapy used in the study takes advantage of a viral vector that I worked on years ago in my lab at the Dana Farber Cancer Institute with my colleagues Joe Sodroski and Mark Poznansky. At the time, we were studying retroviruses — mainly HIV — which is a type of virus that replicates by inserting a copy of its RNA genome into the DNA of a host cell. Before HIV came along, the common belief was that retroviruses could only enter cells and insert RNA while the cells are dividing. This limited the virus’ ability to reproduce. But with HIV, we found it was able to enter cells that were quiescent, essentially dormant cells not yet dividing. This was a critical benefit to the virus — if it could enter dormant and non-dormant cells alike to drop its genetic payload, its ability to thrive was increased exponentially.
At the time we realized the potential impact of this new discovery. If you could remove the fangs of the AIDS virus, rendering it free of its disease-causing genetic material, you could conceivably insert new genetic material into its viral genome and create a path to rapid replication and a cure for the disease. We were confident enough with the approach that we even patented the idea, with the hope of using these viral vectors to develop a treatment for HIV.
In the SCID study, the UCLA and Great Osmond researchers used these same viral vectors, called lentivirus vectors, in their treatment. They removed blood-forming stem cells of each patient, then used a disabled AIDS virus to insert the healthy genetic material the patient was lacking. When the cells were returned to the patient through an intravenous infusion, the retrovirus did its trick with the new material — replicating quickly throughout the body, essentially curing the child of the disease. Whether the cure will last a lifetime is still to be seen, but at least at the three-year mark the results are very encouraging.
While I am delighted by the results of this study alone, I am also very pleased by the thought of what more could come from this next stage of discovery in gene therapy. Scientific discoveries are based on incremental progress. A delicate thread ties our early work on retroviruses to this SCID discovery and even to the mRNA-based Covid vaccines distributed today. The vaccines use an entirely different approach but the same concept is at play — use RNA to teach our bodies how to respond to a disease more effectively. Generations of well trained virologists working on a myriad of diseases have allowed us today to shed light on some of the darkest corners of human biology. With continued investments in this type of research over time, imagine what more we could do.