Metachromatic leukodystrophy (MLD) is an inherited and fatal lysosomal storage disease for which very limited treatment options are available. It arises from mutations in the arylsulfatase A (ARSA) gene which essentially leads to accumulation of fats (sulfatides) in cells and this particularly affects nerve cells, both in the central and peripheral nervous system. This then causes progressive demyelination and devastating neurodegeneration.
Children affected with MLD can present with early-onset or early-juvenile forms and it is the early-onset type (where symptoms appear before 30 months of age) which is the most aggressive and severe; death usually occurs within a few years from presentation. Treatment with haematopoietic stem cell transplant has been reported but usually only affords a delay in progression of symptoms and no improvement in the peripheral nervous system has been seen.
Haematopoietic stem cell (HSC) gene therapy using lentiviral vectors has been developed for a number of metabolic conditions including lysosomal storage diseases with promising results, most notably for adrenoleukodystrophy (ALD) (Cartier et al, 2009). The premise is that gene modified HSCs engraft in the bone marrow and these cells (along with their progeny) act almost as a reservoir, secreting the missing enzyme which enters the circulation and can be delivered to the nervous system where it is needed, a mechanism known as ‘cross-correction’.
Last month Alessandra Biffi’s group published very encouraging interim results from an ongoing Phase 1/2 clinical trial of HSC gene therapy for early-onset MLD in the Lancet (Sessa et al, 2016). In this paper they describe 9 patients who have received gene corrected HSCs following a myeloablative conditioning regime. All are alive with no serious adverse events related to the gene corrected cells at a median follow up of 3 years (18-54 months).
Seven patients were infused whilst pre-symptomatic and two patients showed some early symptoms. ARSA activity was seen in blood cells and cerebrospinal fluid (CSF) from all patients and disease onset was prevented or disease progression halted in 8 of these children resulting in clinical benefit. Gross motor performance for 6 patients was comparable with that of unaffected children of a similar age. Three patients also showed signs of improvement in the peripheral nervous system. Engraftment of gene corrected HSCs in the bone marrow was sustained.
The trial aims to treat 20 patients in total and final results will be published when all patients have reached a follow up of at least three years but this early data suggests that gene therapy may offer a safe and effective treatment for this life-limiting condition. And the earlier children are treated in their disease the better…
Cartier, N., Hacein-Bey-Abina, S., et al. (2009). Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 326(5954): 818-823
Sessa, M., Lorioli, L., et al. (2016). Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. The Lancet. 388(10043): 476-487