Gene therapy using autologous hematopoietic stem cells appears safe and effective as a treatment for early-stage cerebral adrenoleukodystrophy, according to an interim analysis of results from the STARBEAM study.
X-linked adrenoleukodystrophy is characterized by a defect in the ABCD1 gene, leading to progressive demyelination that most commonly presents as learning and behavioral changes in boys aged 3-15 years. The only effective treatment to date has been allogeneic hematopoietic stem cell transplants, but these come with considerable risks, including graft-versus-host disease and graft failure.
The study enrolled 17 boys, all with early-stage cerebral adrenoleukodystrophy and gadolinium enhancement on MRI, and treated them with a single infusion of the autologous cells, then followed them for a median of 29.4 months ( ).
The interim analysis found 14 of the 17 patients (88%) were alive, without any major functional disability and with minimal clinical symptoms. There was no incidence of graft-versus-host disease and no treatment-related deaths.
Lesion progression stabilized in 12 of the 17 patients, and gadolinium enhancement resolved by month 6 in the 16 patients who could be evaluated. It did enhance again in six patients by month 12 but then resolved again later.
One patient in the study experienced a seizure, which led to an increase in the neurologic function score. The remaining two patients had disease progression. One was withdrawn from the study and later died from complications associated with an allogeneic transplant, while the other showed rapid deterioration following treatment and later died from a viral infection complicated by rhabdomyolysis and acute kidney and liver failure.
The latter patient “had a rapid increase in both the Loes score and the score on the neurologic function scale as early as 2 weeks after treatment, findings that suggested that he may have had marked disease progression before treatment,” wrote , of Massachusetts General Hospital and Harvard Medical School, Boston, and his coauthors. “Similar to allogeneic transplantation, hematopoietic stem-cell gene therapy is not expected to have an effect on the phenotypes of adrenomyeloneuropathy or adrenal insufficiency.”
The study found no evidence of integration of the altered ABCD1 gene near sites previously associated with serious adverse events with gene therapy, such as MDS1, EVI1, and LMO2.
The lentiviral vector used in the study also appeared to avoid mutagenesis associated with viral integration, which has been seen in patients treated with gamma-retroviral vector gene therapy, although the authors noted that longer follow-up and larger sample sizes were needed to confirm this.
Neither hematopoietic stem cell transplantation nor gene therapy appeared to prevent the progression of white matter lesions in the first 12-18 months after treatment, the authors wrote.
“Microglial cell death appears to play an important role in the pathophysiology of cerebral adrenoleukodystrophy, and therefore early disease progression may occur during the time before the replacement of microglial cells,” they wrote. “Our data, and the results of studies of allogeneic transplantation, show that some disease progression on MRI during the first year after transplantation is common, and therefore reinforce the urgency in identifying cerebral disease early and treating it swiftly.”
Bluebird Bio, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Great Ormond Street Hospital, and the University College London Great Ormond Street Institute of Child Health Biomedical Research Centre supported the study. Nine authors declared financial ties to Bluebird Bio, and four authors were employees of Bluebird Bio. One author declared personal fees from a pharmaceutical company involved with lentiviral vectors and a patent related to enhanced lentiviral vector expression, and another two authors declared fees and funding from other pharmaceutical companies unrelated to the study.