Gene Therapy Cures ‘Bubble-Boy Disease’

A novel gene therapy generated a functional immune system with all three types of lymphocytes for infants with newly-diagnosed X-linked severe combined immunodeficiency (SCID-X1, or XSCID), a phase I/II trial showed.

Among eight infants treated, seven had normalization of the number of CD3+, CD4+, and naive CD4+ T cells and natural killer (NK) cells by 3 to 4 months after infusion along with reconstitution of B cells, myeloid cells, and bone marrow progenitors corrected by the gene-therapy vector, delivered as an autologous bone marrow transplant.

One infant had little response initially but a second dose of gene-corrected bone marrow stem cells (given without chemotherapy preconditioning) normalized T cell levels and, like the other recipients, cleared preexisting infections and is growing normally, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and colleagues reported in the New England Journal of Medicine.

Seven of the eight infants treated have developed and retained normal levels of immunoglobulin M antibodies, made by B cells as a marker of innate and adaptive immunity. Four had sufficient recovery of B-cell function to stop taking monthly intravenous immunoglobulin (IVIG) therapy, with three of these having responded to standard childhood vaccines, “indicating good B-cell function.”

Without treatment, SCID-X1 causes the body to produce no T cells or NK cells and B cells that are normal in number but not functional.

Clinical Implications

“This therapy has cured the patients and completely reconstituted their immune system,” said Mamcarz at a press briefing held by St. Jude’s.

“While it might not sound like such a big deal that they treated eight infants and they did well, in fact it is a huge step forward,” commented Kathleen Sullivan, MD, PhD, chief of allergy immunology at Children’s Hospital of Philadelphia, in an interview monitored by hospital media relations.

Charlotte Cunningham-Rundles, MD, PhD, a clinical immunologist at Mount Sinai Hospital in New York City who was not involved in the trial, agreed.

“I think you’re going to have to end up calling it a big step,” she told MedPage Today, noting that the outcomes were probably at least on par with the best current treatment — bone marrow transplantation from a matched sibling.

Even for the minority of patients who have a matched donor, gene therapy could be preferable due to the more complete immune recovery than often seen with bone marrow transplant, Mamcarz noted. But such patients were excluded from the study, so a larger experience and longer follow-up would be necessary to determine if it’s worthwhile to test it in patients who do have another source of functional stem cells, she suggested.

Prior gene therapy attempts in SCID-X1 have restored T cells but not B-cell and NK-cell immunity. Moreover, they were complicated by leukemia caused by the gene-therapy retrovirus accidentally turning on adjacent genes that regulate growth.

“This is the best tool we have thus far for gene therapy,” said Mamcarz. “All the active parts of the virus have been taken out with only a shell remaining. This virus is able to effectively deliver the healthy copy of the gene into the stem cells in a way that was not possible before. We believe that this type of virus is safer and more effective for gene therapy. The vector also has been designed with insulators, which protects the site where the vector lands in a cell from activating unintended genes that could cause side effects.”

Also, the effect appears to be more durable with the new design, she noted. “On previous gene therapy trials, waning of the immune system was observed much much earlier, within the first year post-gene therapy. Our longest follow-up thus far is exceeding 2.5 years and that immune system seems to be durable.” (Follow-up as reported in the NEJM paper ranged from 6.7 to 24.9 months in the eight patients.)

“The hallmark of this disease is infection,” and all the patients treated presented with severe, life-threatening disease, she noted. The protective isolation required for these children that gave rise to the “bubble boy disease” moniker was able to be removed within 3 to 4 months after gene therapy, and they returned home to their families. “They are all toddlers now, exploring life, attending daycare, and this part has been extremely rewarding.”

Low Treatment Risk

The Lentiviral Vector SCID-X1 Newly Diagnosed (LVXSCID-ND) phase I/II trial included eight consecutive infants (median age 3.5 months) newly diagnosed with the disorder at two centers and who lacked suitable sibling bone marrow donors.

Their bone marrow was collected and processed at a central facility to enrich for stem cells that were then transfected with the lentivirus for gene therapy. Before reinfusion, patients got individualized doses of nonmyeloablative busulfan chemotherapy for a “cumulative AUC of 22 mg × hour per liter, which is approximately 25% of the typical cumulative AUC used for allogeneic hematopoietic stem-cell transplantation,” the researchers noted.

That’s important because there have been neural development concerns with busulfan use by infants, Cunningham-Rundles noted. “That lesson of how they did it is going to end up being a recipe for everybody.”

Also, it’s another respect in which gene therapy could hold an advantage over bone marrow transplant from a matched donor, added Sullivan.

“One of the standard toxicities of a standard bone marrow transplant is exposure to the conditioning agents (chemotherapy). They acquire, in some cases, sterility or other damage that’s related to the use of those agents,” she said. “There are lots of reasons to think that gene therapy … really ought to be much safer for children and have better preservation of all of their end-organ function.”

In the study, there were only low-grade acute toxic effects during a median follow-up of 16 months.

In the original studies, leukemia developed within 12 to 15 months, noted coauthor Stephen Gottschalk, MD, also of St. Jude’s. “We looked very closely at vector site integration site analysis. … We have not observed clonal evolution in the patients we have treated. So there is right now no early evidence of even a premalignant state in the patients we have treated so far.”

“There remains a theoretical risk but so far with this type of vector (i.e., self-inactivating, or SIN, configured vector), no leukemias have been observed in any of the current HIV-based lentiviral vector studies including in patients with hemoglobinopathies and other diseases such as adrenoleukodystrophy or metachromatic leukodystrophy,” commented Hans-Peter Kiem, MD, PhD, director of the stem cell and gene therapy program at the University of Washington in Seattle.

Broader Applicability

Mustang Bio, which is developing the lentiviral gene therapy for commercial use as MB-107, noted in a press release that the therapy is being considered for a broader range of patients.

“In addition to the newly diagnosed infants with XSCID, we believe there are hundreds of patients with the disease who have been treated with hematopoietic stem cell transplantation, but who are experiencing decreasing T cell immunity and increasing incidence of infections. Through our collaborations with St. Jude and NIH, we are working to offer this life-saving therapy to these patients as well,” said Mustang Bio CEO Manuel Litchman, MD.

That’s important given that X1 is a fairly common type of SCID and that all states now have a newborn screening program for it as of December 2018, so more of these cases will be found, Cunningham-Rundles noted.

This lentiviral gene therapy may find a role beyond immune disorders, too.

“Any genetic disorder with a known genetic defect is amenable to this approach,” Mamcarz said. “We are exploring other immunodeficiencies, but also this vector could potentially be used to treat sickle cell disease.”

A separate but similar gene therapy (Strimvelis) has been approved in Europe for another type of SCID, one arising from a defect in the gene for adenosine deaminase. However, uptake has been low.

Direct gene repair with CRISPR is also in the early stages of testing for SCID-X1, but many safety questions must be answered first, noted Gottschalk.