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Long-Term Follow-Up of Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy
Pierre Bougnères1,2,3, Salima Hacein-Bey-Abina4,5, Ivan Labik6
1UMR1195 INSERM, Le Kremlin Bicêtre, France.
Insights
Lentiviral gene therapy for cerebral adrenoleukodystrophy (c-ALD) halted demyelination in boys but neurological decline occurred in most, suggesting earlier treatment or improved vectors are needed.
Area of Science:
- Neurology
- Genetics
- Biomedical Engineering
Background:
- Cerebral adrenoleukodystrophy (c-ALD) is a fatal demyelinating brain disease.
- Hematopoietic stem cell gene therapy offers a potential treatment for patients lacking a bone marrow donor.
Purpose of the Study:
- To evaluate the long-term clinical and MRI outcomes of lentiviral (LV)-based gene therapy for c-ALD.
- To assess the safety and durability of LV gene therapy in patients with c-ALD.
Main Methods:
- Four boys with c-ALD received LV-based gene therapy targeting the ABCD1 gene.
- Long-term follow-up included clinical assessment, MRI, and analysis of vector genome copies, ALDP expression, and integration sites.
Main Results:
- Demyelination arrested in all patients post-transplant.
- Three of four patients experienced significant cognitive decline within years.
- Transgene expression decreased over time but transduced cells persisted, with no observed adverse effects.
Conclusions:
- LV gene therapy can durably arrest demyelination in c-ALD.
- Neurological deterioration in most patients highlights the need for earlier intervention or more effective therapies.
- Gene therapy shows promise but requires optimization for long-term neurological benefit in c-ALD.
Abstract:
In 2009, cerebral adrenoleukodystrophy (c-ALD) became the first brain disease to be treated with lentiviral (LV)-based hematopoietic stem cell gene therapy with the ABCD1 gene in four boys (P1-P4) who had demyelinating lesions expected to be lethal in the short term and no bone marrow donor. We report the clinical and magnetic resonance imaging (MRI) follow-up over a mean of 8.8 years posttransplant. In parallel, vector genome copies, expression of transgenic ALD protein (ALDP), and viral integration sites were determined in peripheral blood cells. Prior to transplant, the four patients had a normal or near normal neurocognitive status but gadolinium-enhanced demyelination in various brain regions. Gadolinium diffusion disappeared during the first year posttransplant. P3 kept a near normal status until 8.3 years of follow-up, but P1, P2, and P4 showed major cognitive degradation around 9, 28, and 60 months posttransplant. Neurological status and demyelination stabilized until last evaluation in P2, but deteriorated in both P1 at 10 years and P4 at 3 years posttransplant. The proportion of myeloid and lymphoid cells expressing transgenic ALDP decreased by half within 5 years then stabilized around 5% to 10%. Integration site analysis revealed a durable polyclonal distribution of genetically corrected hematopoietic cells. No adverse effects were observed. The long-term arrest of demyelination at MRI and persistence of transduced hematopoietic progenitors support that LV gene therapy may be a safe and durable treatment of c-ALD. However, the neurological degradation observed in three out of four patients mitigates the benefit of this therapy, calling for an earlier intervention, more potent vectors, and additional therapeutic strategies.
