A clinical trial carried out in several countries has just ended. This test, called ’open phase 2-3’, 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% of boys aged 4 to 8 born with a mutation in the ABCD1 gene. These boys with ALD quickly begin to lose their walk and speech. In the New England Journal of Medicine, researchers just described a clinical trial using a lentivirus to infuse a normal copy of the ABCD1 gene into the bone marrow of boys with ALD. The corrected protein stopped the progression of the disease. It is the first effective gene therapy treatment to stop fatal brain disease.

Hematopoietic stem cell gene therapy for cerebral adrenoleukodystrophy

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

CONTEXT

In X-linked adrenoleukodystrophy, mutations in the ABCD1 gene lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterised by demyelination and neurodegeneration. The progression of the disease, which leads to loss of neurological function and death, can only be stopped with an allogeneic hematopoietic stem cell transplant.

METHODS

We recruited boys with cerebral adrenoleukodystrophy in a phase 2-3, open-label, single-arm safety and efficacy study. When screened, patients had to be at an early stage of the disease and show a signal on magnetic resonance imaging (MRI) with the contrast agent gadolinium. The experimental therapy involved the infusion of autologous CD34 + cells transduced with the lentiviral vector elivaldogene tavalentivec (Lenti-D). In this interim analysis, patients were assessed for graft-versus-host disease onset, death, and major functional disabilities, as well as for changes in neurological function and the extent of visible lesions by MRI. The main end goal  was to be alive and have no major functional disability 24 months after the 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 months). Following the transplant, all patients had cells marked with the gene, with no evidence of preferential integration near known oncogenes or clonal outgrowth. A measurable ALD protein was observed in all patients. No treatment-related death or graft-versus-host disease has been reported; 15 of 17 patients (88%) were alive and without major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurological deterioration, died from the progression of the disease. Another patient, who had signs of disease progression on MRI, withdrew from the study to undergo an allogeneic stem cell transplant and later died of transplant-related complications.

CONCLUSIONS

Initial results from 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. Further follow-up is necessary to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio et al., STARBEAM ClinicalTrials.gov, NCT01896102; ClinicalTrialsRegister.eu number, 2011-001953-10.)

Reference: Eichler, F., Duncan, C., Musolino, PL, Orchard, PJ, De Oliveira, S., Thrasher, AJ, Armant, M., Dansereau, C., Lund, TC, Miller, WP, et al . (2017). Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N. Engl. J. Med. Oct 26; 377 (17): 1630-1638