Abstract
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in both glial cells and neurons. MLD results from an inherited deficiency of arylsulfatase A (ARSA) and myelin degeneration in the central and peripheral nervous systems. Currently, no effective treatment is available for the most frequent late infantile (LI) form of MLD after symptom onset. The LI form results in rapid neurological degradation and early death. ARSA enzyme must be rapidly and efficiently delivered to brain and spinal cord oligodendrocytes of patients with LI MLD in order to potentially stop the progression of the disease. We previously showed that brain gene therapy with adeno-associated virus serotype rh10 (AAVrh10) driving the expression of human ARSA cDNA alleviated most long-term disease manifestations in MLD mice but was not sufficient in MLD patient to improve disease progression. Herein, we evaluated the short-term effects of intravenous AAVPHP.eB delivery driving the expression of human ARSA cDNA under the control of the cytomegalovirus/b-actin hybrid (CAG) promoter in 6-month-old MLD mice that already show marked sulfatide accumulation and brain pathology. Within 3 months, a single intravenous injection of AAVPHP.eB-hARSA-HA resulted in correction of brain and spinal cord sulfatide storage, and improvement of astrogliosis and microgliosis in brain and spinal cord of treated animals. These results strongly support to consider the use of AAVPHP.eB-hARSA vector for intravenous gene therapy in symptomatic rapidly progressing forms of MLD.
Highlights
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder (LSD) caused by an inherited deficiency of arylsulfatase A (ARSA; EC 3.1.6.8) (Gieselmann and Krägeloh-Mann, 2006)
The viral constructs for pAAVPHP.eB-CAG-hARSA-HA contained the expression cassette consisting of the human ARSA genes, driven by a CMV early enhancer/chicken β-actin (CAG) synthetic promoter surrounded by inverted terminal repeats (ITR) sequences of AAV2
Vector injection resulted in a widespread transduction of central nervous system (CNS), with a mean of 2.71 ± 0.76 vector genome copies per cell (VGC) in the cortex, 1.6 VGC ± 0.90 in the striatum, 2.3 VGC ± 0.96 in the pons, 1.2 VGC ± 0.37 in the remaining forebrain, 0.5 VGC ± 0.17 in the cerebellum and 1.6 VGC ± 0.50 in the spinal cord (Figure 1A) in treated mice
Summary
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder (LSD) caused by an inherited deficiency of arylsulfatase A (ARSA; EC 3.1.6.8) (Gieselmann and Krägeloh-Mann, 2006). A clinical trial using autologous hematopoietic stem cell transplantation of CD34 cells corrected with lentiviral vector overexpressing human ARSA (HSCT-GT) has shown very encouraging results and provides strong evidence of clinical benefit in presymptomatic patients with late infantile MLD (LI-MLD) and pre or early symptomatic patients with early juvenile MLD (EJMLD; NCT015601821) (Biffi et al, 2013; Sessa et al, 2016). This treatment will likely become the gold standard treatment for pre-symptomatic MLD patients. A phase II-III clinical trial is ongoing (NCT03771898; see text footnote 1) to evaluate the efficacy profile
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