Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy

Type of study: Clinical trial
Patients: 2 children suffering from X-linked adrenoleukodystrophy
Laboratory: Pr Patrick Aubourg & Dr Nathalie Cartier, Inserm U-745, Paris, France.

X-linked adrenoleukodystrophy (ALD) is a fatal demyelinating disease of the central nervous system. Affected children enter a phase of active brain demyelination between 6 and 8 years old. Most die before reaching adolescence. The disease is due to a deficit in the ALD protein, an ABCD-type transporter (ABCD for ATP-Binding Cassette of the D family), located in the membrane of peroxysomes and encoded by the ABCD1 gene. The ALD protein participates in the degradation of very long chain fatty acids (VLCFA) by peroxysomes in myelin cells. The deficiency of this protein disrupts myelin maintenance by these cells.

The disease progression can be halted by allogeneic hematopoietic stem cells transplantation when performed at an early stage of the disease. Beyond that stage, demyelination cannot be stopped. Unfortunately, allogeneic hematopoietic stem cells transplantation cannot be offered to a large number of patients because of the limited number of matched donors and the important associated risk of mortality.

A gene therapy trial was initiated in two children with ALD, aged 7 and 7 and half years, with no bone marrow matched donor but with a progressive cerebral demyelination and adrenal insufficiency. Before therapy, no ALD protein was detectable in the patients’ skin and white blood cells.

CD34+ cells were harvested from the blood of these children and then genetically corrected ex-vivo by the lentiviral vector CG1711 hALD derived from the inactivated HIV-1 and encoding for the normal ABCD1 gene. Before using the corrected cells, extensive tests were performed to evaluate the safety of the lentiviral vectors. Once the tests validated, the children received a full myeloablative conditioning regimen with cyclophosphamide and busulfan aiming at destroying the patient’s bone marrow cells. The corrected cells (4.6 and 7.2 x 106 cells per kilogram for patient 1 and 2 respectively) were then infused to the patients. The bone marrow reconstitution occurred at days 13 to 15 after transplant.

After 24 to 30 months of follow-up, 10 to 15% of the patients’ blood mononuclear cells still express the ALD protein. The normal ABCD1 gene was expressed by these cells four to five times higher than the mutated gene. Also, 20 to 24 months after transplant, VLCFA were reduced by 38% in the plasma of the patients. From a neurological point of view, the cerebral demyelinating lesions in these two children progressed until months 14 and 16 after transplant but have remained stable since then. In addition, the demyelinating lesion observed in the auditory pathway of one patient was reversed.

The arrest of progressive cerebral demyelination in these two children treated by gene therapy represents a clinical outcome comparable to that achieved by allogeneic hematopoietic stem cell transplantation in ALD.