Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

Abstract

Background: 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.

Methods: 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.

Results: 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 Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.

Conclusions: 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. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).

Figure 1. Vector Copy Number and Expression of ALD Protein

Panel A shows the vector copy number in the Lenti-D drug product at infusion and in the peripheral blood for each of the 17 patients at 6 months after infusion. Panel B shows the vector copy number in the peripheral blood for each of the 17 patients at various time points after infusion. Panel C shows the expression of ALD protein in CD14+ cells in the peripheral blood at various time points after infusion; the horizontal lines in the boxes are median percentages, the top and bottom of the boxes are interquartile ranges, and the I bars are minimum and maximum percentages.

Figure 2. Neurologic Function and Clinical Outcomes Relative to Vector Copy Number in the Drug Product

Panel A shows the scores on the cerebral adrenoleukodystrophy–specific neurologic function scale (which ranges from 0 to 25, with higher scores indicating more severe deficits) for each of the 17 patients at various time points after the infusion of the Lenti-D drug product; 12 patients had scores of 0 at all time points, with the last measurement obtained at month 36 (in 3 patients), month 30 (2), month 24 (5), or month 18 (2). The scale is used to evaluate the severity of gross neurologic dysfunction through an assessment for 15 disabilities across multiple domains; a score of 0 indicates the absence of clinical signs of cerebral disease. Panel B shows the clinical outcomes in the patients relative to the vector copy number in the drug product. Green circles represent patients with stable disease, and red triangles represent patients with a change in status. A change in neurologic function was defined as any change from baseline in the score on the neurologic function scale.

Figure 3. Extent of Lesions on MRI

Shown are the Loes scores for each of the 17 patients at various time points after the infusion of the Lenti-D drug product. The Loes scores range from 0 to 34, with higher scores indicating an increased extent of lesions on magnetic resonance imaging (MRI). A score of 0.5 or less is considered to be normal.

Figure 4. Gadolinium Enhancement on MRI

Shown are the results of assessments for gadolinium enhancement on MRI for each of the 17 patients at various time points after the infusion of the Lenti-D drug product. Gadolinium enhancement on reemergence after initial resolution was uniformly more diffuse than the enhancement seen at baseline but was still assessed as positive. Patient 2016 withdrew from the study at month 13. To review the MRIs, see Figure S5 in the Supplementary Appendix.