KANSAS CITY, MO—Lentiviral gene therapy halts inflammation and demyelination in patients with cerebral adrenoleukodystrophy (ALD), according to research presented at the 46th Annual Meeting of the Child Neurology Society and published in the New England Journal of Medicine. The treatment appears to stabilize neurologic function and to have an acceptable safety profile.
ALD is an X-linked genetic disease caused by a defect in ABCD1, which encodes the peroxisomal ABC half-transporter ALD protein. The defect results in abnormal breakdown of very-long-chain fatty acids, which build up and affect tissues in the nervous system. The most common phenotype of ALD is adrenomyeloneuropathy, which involves axonal degeneration in the spinal cord. A more severe phenotype is childhood cerebral adenopathy, which manifests as an inflammatory demyelination in the white matter.
Allogeneic bone marrow transplantation is the only other treatment with proven efficacy in childhood cerebral ALD. It halts disease progression and improves survival in presymptomatic patients. Finding a donor with identical human leukocyte antigen often is difficult, however. In addition, the treatment entails risks of graft failure and graft-versus-host disease, and the rate of treatment-related mortality is greater than 10%. Gene therapy “may be an alternative to allogeneic bone marrow transplantation, particularly for patients who do not have a matched sibling donor who are at risk for graft failure and graft-versus-host [disease],” said Florian Eichler, MD, Director of the Leukodystrophy Service at Massachusetts General Hospital for Children in Boston.
Researchers Transduced Stem Cells Ex Vivo
In the first trial of its kind, Dr. Eichler and colleagues investigated the safety and efficacy of gene therapy with autologous hematopoietic stem cells for cerebral ALD. The enrollment criteria for the phase II–III, single-arm, open-label study were identical to those for conventional bone marrow transplantation, said Dr. Eichler. Eligible participants were age 17 or younger, had a defect in ABCD1, and had evidence of an active, inflammatory lesion on brain MRI. Children with sibling donors for bone marrow transplantation were excluded from the study.
The investigators obtained CD34+ cells from participants through apheresis and transduced them ex vivo with a lentiviral vector containing normal ABCD1. After undergoing conditioning with busulfan and cyclophosphamide, the patients received an infusion of the transduced CD34+ cells. Patients were assessed regularly for graft-versus-host disease, death, and major functional disabilities. Dr. Eichler and colleagues also monitored participants for changes in neurologic function and increases in MRI lesions. At the end of a two-year follow-up period, patients were offered enrollment in a 13-year long-term follow-up study. The main study’s primary end point was being alive and having no major functional disability at 24 months.
Lesion Progression Stabilized in Most Patients
Dr. Eichler and colleagues treated 17 patients with a mean age at enrollment of 6. Participants’ median Loes score at baseline was 2.0, which indicated a low level of neurologic progression. All patients had an ALD neurologic function scale score of 0 at baseline, indicating an absence of clinical signs of cerebral disease.
The vector copy number in peripheral blood ranged from 0.10 to 1.55 in the 14 patients assessed at month 24. At month 36, the number ranged from 0.36 to 1.83 in the three patients assessed. The number had generally stabilized by two months after infusion. The investigators did not observe preferential integration in or near genes that have previously been associated with serious adverse events related to gene therapy (eg, MDS1, EVI1, and LMO2). All participants had expression of ALD protein in peripheral-blood leukocytes at the most recent follow-up (median follow-up time was 29.4 months). The median percentage of CD14+ cells that expressed ALD protein was 19% at 24 months.
Of the 17 patients, 15 were alive at 24 months and maintained an ALD neurologic function scale score of 0 or 1. In untreated patients, ALD neurologic function scale score usually increases significantly after the first symptoms appear. One patient in the study was progressing rapidly at the time of enrollment and subsequently died of disease progression. Another patient with disease progression on MRI withdrew from the study after the infusion and subsequently died from the complications of an allogeneic transplantation. These deaths were considered not to be directly related to treatment. Overall, “the outcome of these 17 patients is dramatically different from what you would see in a cohort of untreated patients,” said Dr. Eichler.
An exploratory analysis indicated that participants with higher vector copy number in their peripheral blood tended to have better neurologic outcomes, while participants with lower vector copy number tended to have poor neurologic outcomes.
Lesion progression, as measured with the Loes score, had stabilized in 12 of the 17 patients (71%) at the time of the interim analysis. “Half the patients stabilized immediately in their Loes scores after treatment. The other half tended to progress within the first 12 months and then stabilize over time,” said Dr. Eichler.
Gadolinium enhancement resolved in 16 of 17 patients by six months. It reappeared in some patients after treatment, although it was much fainter and more poorly circumscribed, compared with the time of screening, said Dr. Eichler.
The investigators did not observe graft failure or graft-versus-host disease in the population. Most adverse events associated with the treatment were consistent with those associated with myeloablative chemotherapy and occurred during conditioning or during the first two weeks after the infusion. One serious adverse event that possibly was related to treatment was hemorrhagic cystitis associated with BK virus, which resolved with conservative measures.
The results have implications for leukodystrophies in general, according to Dr. Eichler. “Specific phenotypes, even within the same individual leukodystrophy, require different approaches” such as ex vivo or in vivo gene therapy, he added. Overall, the safety data are reassuring, and gene therapy appears to have encouraging efficacy in ALD, he concluded.
Eichler F, Duncan C, Musolino PL, et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med. 2017;377(17):1630-1638.
Engelen M. Optimizing treatment for cerebral adrenoleukodystrophy in the era of gene therapy. N Engl J Med. 2017;377(17):1682-1684.