Gene Therapy for X-Linked SCID

Gene Therapy for X-Linked SCID


[Music] As a newborn, Max Agit was diagnosed with X-linked severe combined immunodeficiency, or SCID-X1. This rare disorder is caused by gene mutations that prevent infection-fighting immune cells from developing and functioning normally, leaving affected babies susceptible to severe infections. In 1991, Max received a bone marrow transplant from one of his parents, but this life-saving treatment in many cases only partially restores immunity. “I was out of elementary school at the time, months at a time, you know. I was probably spending more time in the hospital than in school at one point.” Max later received a second transplant but needed regular infusions of IgG, a type of antibody, to bolster his immune system. “My situation, you know, was not terrible, but I felt it could be a lot better.” Max came to the National Institutes of Health, or NIH, where Dr. Harry Malech and his team were developing a new gene therapy. Previously, other researchers had used gene therapy to restore immunity in infants with SCID. “So we said, well, this is working in infants. Let’s here at the NIH see if we can rescue some of these older children, who are, who are post-parental transplant but who still have a whole variety of medical problems.” Max was the first patient to receive the new treatment. “I figured, you know, I want to take a chance. Sometimes you do have to take risks to make improvements, and this for me was my personal chance to make that improvement.” First, Max took medications to coax some blood-forming stem cells with the defective gene out of his bone marrow and into the blood. Then, he underwent apheresis, in which blood is withdrawn and passed through a machine that separates blood components. All but the stem-cell-containing component were returned. The researchers exposed purified stem cells to a viral vector carrying a corrected gene. Dr. Malech and his team collaborated with
researchers at St. Jude Children’s Research Hospital to develop a novel vector called a lentivector. Their new approach also included chemotherapy conditioning to create space in the bone marrow for the corrected stem cells. Finally, they returned the corrected cells to Max. “It’s a surprising non-event. It’s a little 50 mL syringe of cloudy fluid, which has the cells, and we hook it up to the IV line that the
patient has and slowly put it in over 10 minutes and… nothing happens.” In the following months, they monitored Max’s immune status, including levels of IgG and IgM antibodies. “Everything was an unknown. And about his second month we began to see his his serum IgM go up. It started to go up and up and up and up. It worried us. We did a bunch of studies to make sure nothing bad was happening. And then it began to come down.” His IgG levels rose too, and he needed fewer IgG infusions. Eventually, he didn’t need them at all — a huge time and cost savings. “What was remarkable was that he had had a norovirus infection that was years and years and years. And that infection by about a year cleared.” The researchers have since treated more patients. They began to recognize a pattern: the spike in IgM level signaled that the therapy was starting to work. “People have often asked me, ‘Was it the conditioning — that is, the making room in the marrow — or is it this lentivector?’ I think it’s a probably a bit of both that this worked as well as it did.” The researchers plan to test the gene therapy in additional patients and are continuing to monitor those who have received the treatment. “So I’m just now doing a lot of the things that, you know, I maybe should have been doing years ago. And I’m really just enjoying life right now, I’m living for myself I think, right now.” [Music]

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