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Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy
Florian Eichler1, Christine Duncan1, Patricia L Musolino1
1From Massachusetts General Hospital and Harvard Medical School (F.E., P.L.M.), Dana-Farber and Boston Children's Cancer and Blood Disorders Center (C. Duncan, M.A., C. Dansereau, D.A.W.), and Boston Children's Hospital, Harvard Medical School, and Harvard Stem-Cell Institute (D.A.W.), Boston, and Bluebird Bio, Cambridge (A.M.P., E.S., T.O., D.D.) - all in Massachusetts; University of Minnesota Children's Hospital, Minneapolis (P.J.O., T.C.L., W.P.M., G.V.R.); University of California, Los Angeles, Los Angeles (S.D.O., R.S., A.J.S.); University College London Great Ormond Street Hospital Institute of Child Health and Great Ormond Street Hospital NHS Trust, London (A.J.T., H.B.G., P.G.); Pediatric Neurology Department, Hôpital Bicêtre-Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France (C.S., P.A.); Fundacion Investigar, Buenos Aires (H.A.); and Women's and Children's Hospital, North Adelaide, SA, Australia (D.B., N.J.C.S.).
Insights
Lenti-D gene therapy shows promise for treating cerebral adrenoleukodystrophy in boys. This treatment may halt disease progression, offering an alternative to stem-cell transplantation with positive early safety and efficacy results.
Area of Science:
- Genetics and Gene Therapy
- Neurology
- Pediatric Medicine
Background:
- X-linked adrenoleukodystrophy (X-ALD) results from ABCD1 gene mutations, causing ALD protein dysfunction.
- Cerebral X-ALD leads to demyelination, neurodegeneration, and potentially fatal loss of neurologic function.
- Allogeneic hematopoietic stem-cell transplantation is currently the only established treatment to halt disease progression.
Purpose of the Study:
- To evaluate the safety and efficacy of Lenti-D gene therapy in boys with early-stage cerebral X-ALD.
- To assess key clinical outcomes including survival, major functional disability, neurologic function, and MRI lesion progression.
Main Methods:
- A single-group, open-label, Phase 2-3 study enrolled boys with early-stage cerebral X-ALD and MRI evidence of disease.
- Treatment involved infusion of autologous CD34+ cells genetically modified with the elivaldogene tavalentivec (Lenti-D) lentiviral vector.
- Interim analysis assessed graft-versus-host disease, mortality, functional disability, neurologic status, and MRI changes, with a primary endpoint of survival and absence of major functional disability at 24 months.
Main Results:
- 17 boys received Lenti-D gene therapy, with a median follow-up of 29.4 months.
- All patients showed gene-marked cells, ALD protein expression, and no evidence of oncogenic integration or clonal expansion.
- 88% of patients (15/17) were alive and free of major functional disability, with no reported treatment-related death or graft-versus-host disease.
Conclusions:
- Lenti-D gene therapy presents a potential safe and effective alternative to allogeneic stem-cell transplantation for early-stage cerebral X-ALD.
- Further long-term follow-up is necessary to confirm response duration and safety.
- The study suggests a significant improvement in clinical outcomes for treated patients.
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 .).
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