Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ, Armant M, Dansereau C, Lund TC, Miller WP, Raymond GV, Sankar R, Shah AJ, Sevin C, Gaspar HB, Gissen P, Amartino H, Bratkovic D, Smith NJC, Paker AM, Shamir E, O'Meara T, Davidson D, Aubourg P, Williams DA. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017 Oct 26;377(17):1630-1638.
In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation.
We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2–3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion.
A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.
Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety.
Fifteen of 17 boys with cerebral adrenoleukodystrophy (ALD) are doing well after receiving a novel gene therapy, scientists at Massachusetts General Hospital and Boston Children's Hospital reported at the Child Neurology Society annual meeting here in October.
The scientists reported interim results of the STARBEAM trial, an ongoing multicenter, open label phase 2-3 study. Eleven of the 17 boys were treated in Boston and the others were from centers in the United States and Europe. The primary endpoint was being alive and having no functional disability 24 months after infusion of the gene therapy.
“It appears to be the first successful gene therapy treatment to halt a fatal brain disease,” said Florian S. Eichler, MD, director of the leukodystrophy service at the MassGeneral Hospital for Children and lead author of the study that was simultaneously published in the October 26 issue of The New England Journal of Medicine (NEJM).
ALD affects 30 to 40 percent of boys between 4 and 8 years old who are born with a mutation in the X-linked ATP-binding cassette, subfamily D, member 1 (ABCD1) gene. Hyperactivity and behavior changes are often the first sign so the disease is often missed. The boys with ALD quickly begin to lose their ability to walk and talk. By the time a diagnosis is suspected, a brain scan shows a massive lesion in white matter tracts around the corpus callosum….
The boys, whose average age was 6 years old, were identified through screening and family history. They were asymptomatic at the time of the transplant but were accepted into the study because they had evidence of early white matter inflammation on a magnetic resonance imaging (MRI) scan.
One patient in the study died from disease progression. In hindsight, Dr. Eichler said that his disease had been advancing more rapidly at the time of enrollment. Another patient withdrew from the study after the transplant, and his parents decided to have him undergo allogeneic bone marrow transplant. He too died.
The boys are being closely followed. MRI scans show that the early lesions have stopped spreading. There haven't been any engraftment problems or graft-versus-host issues. The 15 boys have minimal or no symptoms, Dr. Eichler said. Two years later, these boys are leading normal lives, he added.
None of the 15 children have more than minimal signs of disease. “The efficacy (ability to stop lesion progression and clinical decline) is similar to what is seen with allogeneic bone marrow transplantation. The difference is that we saw no engraftment and no graft-versus-host disease, complications commonly encountered with allogeneic bone marrow transplantation. We think the procedure is stopping the inflammatory degeneration.”
Dr. Eichler added that eight more boys have undergone the gene therapy since the study was submitted to the NEJM. The Boston team is continuing to enroll patients into the trial and monitoring the boys who had the gene therapy. Bluebird Bio, the biotechnology company that sponsored the trial, plans to apply for federal approval to use the ex-vivo technique for the treatment of ALD. It is not known how much the one-time gene therapy treatment might cost.
The Boston scientists are now working on another gene therapy using the AAV-9 vector to deliver the ABCD1 gene into the intrathecal space in the spinal cord. It worked in animal models, and they are doing more studies before human trials begin. They will recruit adult patients who often have spinal cord defects.