Single‐dose intracerebroventricular administration of galactocerebrosidase improves survival in a mouse model of globoid cell leukodystrophy

Abstract

Globoid cell leukodystrophy (GLD), also known as Krabbe disease, is a devastating, degenerative neurological disorder. It is inherited as an autosomal recessive trait caused by loss-of-function mutations in the galactocerebrosidase (GALC) gene. Previously, we have shown that peripheral injection of recombinant GALC, administered every other day, results in a substantial improvement in early clinical phenotype in the twitcher mouse model of GLD. While we did detect active enzyme in the brain following peripheral administration, most of the administered enzyme was localized to the periphery. Given the substantial central nervous system (CNS) involvement in this disease, we were interested in determining whether or not a single-dose administration of the recombinant enzyme directly to the CNS, which could potentially be achieved clinically, would result in any substantial improvement. Following intracerebroventricular (i.c.v.) administration of GALC we noted a significant, 16.5%, reduction in the GALC substrate psychosine, the abnormal accumulation of which is believed to play a pivotal role in the CNS pathology observed in this disease. Moreover, recombinant GALC was found not only in periventricular regions but also at sites distant to the injection such as the cerebral cortex and cerebellum. Most importantly, animals receiving a single i.c.v. dose of the enzyme at postnatal day 20 survived up to 51 days, which compares favorably to the control twitcher animals, which normally only live to postnatal day 40/42. These results indicate that even a single i.c.v. administration of the recombinant enzyme can have significant clinical impact and suggests that other lysosomal storage disorders with significant CNS involvement may similarly benefit.

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

“…The extension of lifespan reported here is moderate and in line with that observed in Twi mice that underwent other CNS-directed treatments, i.e. transplantation of gene-corrected neural stem cells (NSCs) (15) or mesenchymal stem cells (16), intratechal administration of recombinant GALC (49), and likely reflects failure of these approaches to provide sufficient levels of functional enzyme to correct the somatic pathology and particularly the PNS, which is likely the ultimate cause of lethality in this mouse model. In fact, treatments able to correct the systemic disease associated with GLD, such as HCT, alone or in combination with systemic delivery of GALC-expressing vectors (14,20–23) as well as novel HSC GT protocols (50), significantly extend the lifespan of relevant GLD models.…”

Determination of the role of injection site on the efficacy of intra-CSF enzyme replacement therapy in MPS IIIA mice

“…Ommaya reservoir) would be necessary. Injection of replacement enzyme into ventricular CSF has been carried out in single-injection studies in mouse models of two other lysosomal storage disorders: Krabbe disease [14] and neuronopathic (type II/III) Gaucher disease [39]. Repeat-injection studies have been performed in mice with Niemann-Pick A, Sandhoff disease, neuronopathic Gaucher disease and MPS II [17,[39][40][41], and sustained enzyme delivery (using mini-osmotic pumps) has been explored in late infantile neuronal ceroid lipofuscinosis and metachromatic leukodystrophy mice [15,19].…”

“…Studies in mouse and dog models of MPS IIIA [4][5][6][7][8][9][10][11], in addition to similar studies in other neurodegenerative lysosomal storage disorders, including MPS I [12,13], Krabbe disease [14], Batten's disease [15,16], Niemann-Pick A [17], fucosidosis [18], metachromatic leukodystrophy [19] and MPS II [20]; reviewed in [21], have indicated that intra-CSF injection of recombinant replacement enzyme is effective in reducing or preventing accumulation of primary and secondary substrates and, where assessed, ameliorating clinical disease. The injection site used in many of these investigations has been the cisterna magna, however, ventricular or intrathecal lumbar delivery is also possible, with the former under investigation in an enzyme replacement trial in children with a form of Batten's disease (NCT#01907087), and the latter being utilized in clinical trials in MPS I, MPS II, MPS IIIA and metachromatic leukodystrophy patients (NCT; #00852358; #01506141; #01299727; #0150028; #02060526).…”

Experimental Therapies in the Murine Model of Globoid Cell Leukodystrophy

“…Single dose intracerebroventricular (ICV) administration of GALC increased the Twi lifespan to an average of ~50 days. 31 This mild clinical effect may be due to enzyme turnover, as GALC enzyme is undetectable at the moribund stage. 32 Repeated enzyme injections are necessary to maintain a long-term functional pool of GALC enzyme.…”