Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy

Florian Eichler, Christine Duncan, Patricia L. Musolino, Paul J. Orchard, Satiro De Oliveira, Adrian J. Thrasher, Myriam Armant, Colleen Dansereau, Troy C. Lund, Weston P. Miller, Gerald V. Raymond, Raman Sankar, Ami J. Shah, Caroline Sevin, H. Bobby Gaspar, Paul Gissen, Hernan Amartino, Drago Bratkovic, Nicholas J.C. Smith, Asif M. PakerEsther Shamir, Tara O’Meara, David Davidson, Patrick Aubourg, David A. Williams

Research output: Contribution to journalArticle

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 Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.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

Original languageEnglish (US)
Pages (from-to)1630-1638
Number of pages9
JournalNew England Journal of Medicine
Volume377
Issue number17
DOIs
StatePublished - Oct 26 2017
Externally publishedYes

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Adrenoleukodystrophy
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Genetic Therapy
Nervous System
Disease Progression
Magnetic Resonance Imaging
Stem Cell Transplantation
Graft vs Host Disease
Safety
Investigational Therapies
Hematopoietic Stem Cell Transplantation
Gadolinium
Demyelinating Diseases
Oncogenes
Proteins
Transplantation
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Eichler, F., Duncan, C., Musolino, P. L., Orchard, P. J., De Oliveira, S., Thrasher, A. J., ... Williams, D. A. (2017). Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. New England Journal of Medicine, 377(17), 1630-1638. https://doi.org/10.1056/NEJMoa1700554

Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. / Eichler, Florian; Duncan, Christine; Musolino, Patricia L.; Orchard, Paul J.; De Oliveira, Satiro; Thrasher, Adrian J.; Armant, Myriam; Dansereau, Colleen; Lund, Troy C.; Miller, Weston P.; Raymond, Gerald V.; Sankar, Raman; Shah, Ami J.; Sevin, Caroline; Gaspar, H. Bobby; Gissen, Paul; Amartino, Hernan; Bratkovic, Drago; Smith, Nicholas J.C.; Paker, Asif M.; Shamir, Esther; O’Meara, Tara; Davidson, David; Aubourg, Patrick; Williams, David A.

In: New England Journal of Medicine, Vol. 377, No. 17, 26.10.2017, p. 1630-1638.

Research output: Contribution to journalArticle

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 2017, 'Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy', New England Journal of Medicine, vol. 377, no. 17, pp. 1630-1638. https://doi.org/10.1056/NEJMoa1700554
Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. New England Journal of Medicine. 2017 Oct 26;377(17):1630-1638. https://doi.org/10.1056/NEJMoa1700554
Eichler, Florian ; Duncan, Christine ; Musolino, Patricia L. ; Orchard, Paul J. ; De Oliveira, Satiro ; Thrasher, Adrian J. ; Armant, Myriam ; Dansereau, Colleen ; Lund, Troy C. ; Miller, Weston P. ; Raymond, Gerald V. ; Sankar, Raman ; Shah, Ami J. ; Sevin, Caroline ; Gaspar, H. Bobby ; Gissen, Paul ; Amartino, Hernan ; Bratkovic, Drago ; Smith, Nicholas J.C. ; Paker, Asif M. ; Shamir, Esther ; O’Meara, Tara ; Davidson, David ; Aubourg, Patrick ; Williams, David A. / Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. In: New England Journal of Medicine. 2017 ; Vol. 377, No. 17. pp. 1630-1638.
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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.",
author = "Florian Eichler and Christine Duncan and Musolino, {Patricia L.} and Orchard, {Paul J.} and {De Oliveira}, Satiro and Thrasher, {Adrian J.} and Myriam Armant and Colleen Dansereau and Lund, {Troy C.} and Miller, {Weston P.} and Raymond, {Gerald V.} and Raman Sankar and Shah, {Ami J.} and Caroline Sevin and Gaspar, {H. Bobby} and Paul Gissen and Hernan Amartino and Drago Bratkovic and Smith, {Nicholas J.C.} and Paker, {Asif M.} and Esther Shamir and Tara O’Meara and David Davidson and Patrick Aubourg and Williams, {David A.}",
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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.

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.

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