NEW YORK – Researchers from the University of California, Los Angeles, and University College London are advancing a gene therapy they say could be a cure for severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID). The researchers hope to seek the US Food and Drug Administration's approval to market the gene therapy.
At the American Society of Hematology's annual meeting in San Diego, researchers on Monday reported results from 62 patients in the US and UK treated with this gene therapy, referred to as UCL/A-ADA, within Phase I/II trials and who had at least five years of long-term follow-up data. All treated patients were children between 4 months to nearly 4 years of age.
ADA-SCID is a rare and inherited genetic immune disorder, caused by mutations in the ADA gene, in which patients are born with a lack of functional immune cells and a damaged immune system. Without treatment, patients with ADA-SCID typically die within the first year or two of life.
"We are actively working on a path toward [biologics license application] submission and FDA approval," said Katelyn Masiuk, a researcher at UCLA's David Geffen School of Medicine, who presented results at the conference. The gene therapy development is led by Donald Kohn, a professor of microbiology, immunology, and molecular genetics and pediatric hematology/oncology at UCLA, and Claire Booth, a professor of gene therapy and pediatric immunology at UCL.
Armed with a nearly $15 million grant from the California Institute for Regenerative Medicine, the research team is developing a commercial-grade manufacturing protocol for the vector and the drug product.
Researchers have also founded a for-profit public benefit corporation, Rarity PBC, which will license intellectual property from UCLA and UCL, engage a contract development and manufacturing organization, and develop clinical and regulatory operations to market this gene therapy in the US, should it be approved.
Creating the gene therapy involves collecting a patient's own hematopoietic stem cells, modifying them ex vivo with a lentiviral vector that encodes a functional copy of the ADA gene, and infusing them back into the patient. Within the clinical trials, patients received either a "fresh" drug product administered after manufacturing or a cryopreserved drug product.
In the US, researchers collected cells from patients' bone marrow, and in the UK, they collected cells mainly from patients' mobilized peripheral blood. Researchers have since established that the commercial manufacturing process will use mobilized peripheral blood across sites, Masiuk said.
Most patients who received the gene therapy have experienced sustained improvements in immune function, researchers reported. Fifty-nine of the 62 patients, or 95.2 percent, who received the gene therapy within the clinical trials experienced event-free survival, which researchers defined as survival without needing to restart ADA enzyme replacement therapy or use rescue allogeneic hematopoietic stem cell transplantation. None of the 62 patients have died.
The 59 patients who achieved successful engraftment by six months have demonstrated "durable and safe results," Masiuk said. Fifty-seven of the 59 patients also discontinued immunoglobulin-replacement therapy, a treatment that aims to boost levels of antibodies, at a median of about a year posttreatment.
Patients demonstrated stable production of ADA enzyme, with ADA activity levels normalizing by three months posttreatment, and these results were sustained through their last follow-up visit.
The median length of follow-up was 7.5 years, ranging from five to 11.2 years, as of the data cutoff in December 2023. The first patient to receive this gene therapy was treated in 2012.
The number of immune T cells initially decreased in patients after the conditioning regimen and withdrawal of other therapies, but two years after treatment, most patients' immune T-cell levels were nearly normal or normal and have remained stable for up to 11 years. Researchers saw a similar trend with CD19-positive B cells and with CD56-positive and CD16-positive natural killer cells.
The most common adverse events in the early posttreatment period were consistent with the safety profile of busulfan, a chemotherapy drug used in the conditioning regimen, and immune reconstitution. There were 13 serious adverse events in long-term follow-up, including 12 infections and one related to a planned surgical procedure.
These results affirm UCL/A-ADA "can be a curative option for ADA-SCID," with durable immune reconstitution, sustained ADA enzyme activity, and a strong safety profile, Masiuk said.