A clinical trial conducted in several countries has just been completed. This "phase 2-3 open" trial, confirms the results obtained in 2009 in France by the teams of Patrick Aubourg and Nathalie Cartier.
Florian Eichler, principal investigator of the study, presents the results :
“ Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy ”
« Cerebral adrenoleukodystrophy (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. The boys with ALD quickly begin to lose their ability to walk and talk. In the New England Journal of Medicine, researchers now reported using a lentivirus to infuse a normal copy of the ABCD1 gene into the bone marrow of boys with ALD. The corrected protein stopped disease progression. This is the first successful gene therapy treatment to halt a fatal brain disease. »
Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy
Florian Eichler, M.D., Christine Duncan, M.D., Patricia L. Musolino, M.D., Ph.D., Paul J. Orchard, M.D., Satiro De Oliveira, M.D., Adrian J. Thrasher, M.D., Myriam Armant, Ph.D., Colleen Dansereau, M.S.N., R.N., Troy C. Lund, M.D., Weston P. Miller, M.D., Gerald V. Raymond, M.D., Raman Sankar, M.D., Ami J. Shah, M.D., Caroline Sevin, M.D., Ph.D., H. Bobby Gaspar, M.D., Paul Gissen, M.D., Hernan Amartino, M.D., Drago Bratkovic, M.D., Nicholas J.C. Smith, M.D., Asif M. Paker, M.D., Esther Shamir, M.P.H., Tara O’Meara, B.S., David Davidson, M.D., Patrick Aubourg, M.D., et David A. Williams, M.D.
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 genemarked 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 stemcell 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. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102; ClinicalTrialsRegister.eunumber, 2011-001953-10.)
Eichler, F., Duncan, C., Musolino, P.L., Orchard, P.J., De Oliveira, S., Thrasher, A.J., Armant, M., Dansereau, C., Lund, T.C., Miller, W.P., et al. (2017). Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N. Engl. J. Med. Oct 26;377(17):1630-1638