Therapeutic benefit of lentiviral-mediated neonatal intracerebral gene therapy in a mouse model of globoid cell leukodystrophy

Abstract

Globoid cell leukodystrophy (GLD) is an inherited lysosomal storage disease caused by β-galactocerebrosidase (GALC) deficiency. Gene therapy (GT) should provide rapid, extensive and lifetime GALC supply in central nervous system (CNS) tissues to prevent or halt irreversible neurologic progression. Here we used a lentiviral vector (LV) to transfer a functional GALC gene in the brain of Twitcher mice, a severe GLD model. A single injection of LV.GALC in the external capsule of Twitcher neonates resulted in robust transduction of neural cells with minimal and transient activation of inflammatory and immune response. Importantly, we documented a proficient transduction of proliferating and post-mitotic oligodendroglia, a relevant target cell type in GLD. GALC activity (30–50% of physiological levels) was restored in the whole CNS of treated mice as early as 8 days post-injection. The early and stable enzymatic supply ensured partial clearance of storage and reduction of psychosine levels, translating in amelioration of histopathology and enhanced lifespan. At 6 months post-injection in non-affected mice, LV genome persisted exclusively in the injected region, where transduced cells overexpressed GALC. Integration site analysis in transduced brain tissues showed no aberrant clonal expansion and preferential targeting of neural-specific genes. This study establishes neonatal LV-mediated intracerebral GT as a rapid, effective and safe therapeutic intervention to correct CNS pathology in GLD and provides a strong rationale for its application in this and similar leukodystrophies, alone or in combination with therapies targeting the somatic pathology, with the final aim of providing an effective and timely treatment of these global disorders.

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

“…This is in keeping with our previous observations following intraneural delivery of the same vector (8) or with preclinical (37,38) and clinical (39) applications of similar lentiviral vectors. Rarely reported inflammatory responses (26) were attributed to the reporter gene and not to the intrathecal method of gene delivery or to the vector type.…”

Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients

“…While treatment of ADA-SCID by HSCT or HSC-GT provides metabolic detoxification in the brain, it might be insufficient to provide the stabilizing allosteric support of ADA to Adora signaling locally. Direct delivery of ADA to the CNS through in vivo gene therapy might be explored as recently proposed for other metabolic disorders4243.…”

The Big Bluff of Amyotrophic Lateral Sclerosis Diagnosis: The Role of Neurodegenerative Disease Mimics

“…Indeed, it has been shown that molecules regulating protein sorting and degradation within the endocytic and autophagic pathways (fig. 3a) generally cause disorders associated with lysosomal dysfunctions [57,58,59,60,61,62,63,64,65] and are also a hallmark of several neurodegenerative diseases, including ALS, PD and AD (fig. 3b) [66].…”