A gene therapy developed by St. Jude Children’s Research Hospital has shown tremendous promise to change the outlook for children with a debilitating disease that makes them vulnerable to common infections, according to study results published Wednesday in the New England Journal of Medicine.

In an early-stage trial testing the experimental gene therapy, 10 infants with a rare condition often termed “bubble boy disease” showed marked improvement in the functioning of their immune systems, allowing them to live normal lives, the study’s researchers said.

Encouraged by the results, the hospital’s researchers and leaders went as far as describing the treatment as curative — although, with patient follow-up ranging from six months to two years, questions remain whether it would be lasting.

“From a physiological point of view and from the quality of life of these patients, this is a cure,” said St. Jude CEO James Downing. “The question becomes: Will it be a durable cure? Will it last 10, 20, 50 years for these children? Only time will tell.”

While the therapy’s durability and commercial potential is not yet clear, the effectiveness and safety demonstrated in the Phase 1/2 study speak to the recent growth of the gene therapy field.

Study researchers highlighted advances made since the previous generation of gene therapies for the condition, called SCID-X1. Research hit major speed bumps in the mid-2000s following reports of leukemia in some treated children.

That problem inspired Brian Sorrentino, a physician scientist at St. Jude, to find a way to ensure future therapies wouldn’t lead to leukemia. Working in the hospital’s hematology department, Sorrentino developed a type of genetic regulator designed to prevent viral vectors used in gene therapy delivery from affecting adjacent genes. Such so-called insulators, the thinking went, would curb the cancer risk.

A senior author on the paper, Sorrentino died shortly after the manuscript was submitted for publication.

After a median follow-up of just over 16 months, none of the infants have any signs of developing leukemia. Previous studies found evidence of the cancer emerging between 12 and 15 months, giving researchers at St. Jude confidence that Sorrentino’s approach has worked.

A rare and severe condition

SCID-X1, or x-linked severe combined immunodeficiency, is a genetic condition marked by its rarity and severity. Through a mutation in a gene known as IL2RG, the disease cripples the immune system’s ability to function.

Children affected by the disease require protective isolation and are allowed no contact with the outside world. A common cold virus can be enough to kill them, said Ewelina Mamcarz, one of the study’s authors and a St. Jude doctor.

SCID-X1 is the most common variant of a broader condition that’s been described in the past as “bubble boy disease.” For those with matched stem cell donors, a bone marrow transplant can rescue patients diagnosed in time. However, only about 20% of patients are eligible

Another variant, called ADA-SCID, stems from a genetic deficiency of the adenosine deaminase, or ADA, enzyme. Without ADA, a chemical toxic to immune cells proliferates.

A gene therapy, called Strimvelis and sold last year by GlaxoSmithKline to Orchard Therapeutics, is approved for ADA-SCID in Europe. GSK struggled to commercialize the treatment, however, and only a handful of patients ever received it.

In St. Jude’s trial, the patients were particularly sick, with multiple having already failed allogeneic stem cell transplants. A majority suffered from severe infections before treatment.

Researchers collected patient cells from the bone marrow. They then used a lentiviral vector to insert a corrected IL2RG gene back into the stem cells. After giving patients a preconditioning course of busulfan, cells were reinfused back into the infants. From cell harvest to infusion, the entire process took about 10 days.

Then came the impressive results. The study participants were mostly discharged from the hospital within weeks and are now growing into normal-functioning toddlers, researchers said.

Among the eight patients included in the NEJM article, four no longer required immunoglobulin treatment, a plasma-derived therapy often used for patients with immune disorders. Mamcarz said three more patients have stopped using immunoglobulin in the time since the manuscript was accepted by NEJM.

For three patients, existing infections were resolved. Three others showed antibody responses to vaccination.

That’s made possible by the reconstitution of their immune systems, with these infants showing engraftment of crucial immune cells, including T cells, B cells and natural killer (NK) cells.

“This novel approach has shown really outstanding results for the infants,” Downing said. “The treatment has fully restored the immune system in these patients, which wasn’t possible before, and has no immediate side effects.”

“These patients are responding to vaccination and are able to live normal and healthy lives,” he added.

Questions remain on the scalability and variability of results. One of the patients, for instance, showed poor immune reconstitution and required a second infusion of gene therapy after one year.

And the results showed a wide range of vector copy numbers — a measure of how well the corrected gene was incorporated —​ across the 8 patients included in the NEJM article. Study authors attributed the variability to patient-specific factors.

“We believe that had something to do with the way the stem cells and the bone marrow of these young babies mature and develop over time,” Mamcarz said.

A commercial future?

While the results are impressive, the therapy’s future remains uncertain. Through a licensing deal inked last August, St. Jude’s will transfer the regulatory application allowing clinical testing of the therapy to Mustang Bio, a small Massachusetts-based biotech. Mustang will need to get Food and Drug Administration clearance of its commercial cell processing capabilities to move forward.

Mustang CEO Manny Litchman, speaking to BioPharma Dive in an interview, expects the company will need to start its own trial with the gene therapy, which it has dubbed MB-107. That study will be used to “show some level of comparability” with how the therapy was made by St. Jude’s.

Litchman said he expects only three or four patients would be required, with a shortened follow-up time of six months. But that regulatory plan still needs to pass muster with the FDA.

He said the path forward should become significantly clearer in the latter half of the year following meetings with the regulator.

Beyond the regulatory hurdles, the road to commercialization for gene therapies has yet to be fully paved. The healthcare system is still sorting out sustainable payment models for these potentially curative one-time treatments, with some industry leaders floating ideas of multi-million dollar price tags and installment payment plans.

And the manufacturing challenges for these complex treatments making scaling-up to meet commercial demands no easy task.

With that partly in mind, investment has surged into gene therapy manufacturing. Two leading contractor manufacturers, Thermo Fisher and Catalent, both recently made multi-billion dollar acquisitions in the field.

Still, how well the industry can meet the needs of smaller companies like Mustang is still an open question. By 2020, the FDA anticipates it will receive more than 200 applications to begin clinical gene therapy testing and, by 2025, approvals for between 10 and 20 cell and gene therapy products a year.

In discussing their findings, the NEJM study authors identified manufacturing — particularly the production process for the required viral vectors — as a key element of the therapy’s future.

Another study of St. Jude’s therapy in SCID-X1 patients older than two years of age is ongoing, led by the National Institutes of Health. That study has shown similar, albeit earlier, data which could expand the pool of addressable patients down the line.

Researchers also said the therapy could bring benefit to other diseases, particularly Wiskott-Aldrich syndrome and sickle cell disease.