TY - JOUR
T1 - Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy
AU - Eichler, Florian
AU - Duncan, Christine
AU - Musolino, Patricia L.
AU - Orchard, Paul J.
AU - De Oliveira, Satiro
AU - Thrasher, Adrian J.
AU - Armant, Myriam
AU - Dansereau, Colleen
AU - Lund, Troy C.
AU - Miller, Weston P.
AU - Raymond, Gerald V.
AU - Sankar, Raman
AU - Shah, Ami J.
AU - Sevin, Caroline
AU - Gaspar, H. Bobby
AU - Gissen, Paul
AU - Amartino, Hernan
AU - Bratkovic, Drago
AU - Smith, Nicholas J.C.
AU - Paker, Asif M.
AU - Shamir, Esther
AU - O’Meara, Tara
AU - Davidson, David
AU - Aubourg, Patrick
AU - Williams, David A.
N1 - Publisher Copyright:
Copyright © 2017 Massachusetts Medical Society.
PY - 2017/10/26
Y1 - 2017/10/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85032463285&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85032463285&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa1700554
DO - 10.1056/NEJMoa1700554
M3 - Article
C2 - 28976817
AN - SCOPUS:85032463285
SN - 0028-4793
VL - 377
SP - 1630
EP - 1638
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 17
ER -