Restoration of central nervous system α‐N‐acetylglucosaminidase activity and therapeutic benefits in mucopolysaccharidosis IIIB mice by a single intracisternal recombinant adeno‐associated viral type 2 vector delivery

Abstract

A single IC rAAV2 gene delivery is functionally beneficial for treating the CNS disease of MPS IIIB in mice. It is immediately clinically translatable, with the potential of improving the quality of life for patients with MPS IIIB.

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

“…Different AAV vector serotypes have been tested after intra-CSF delivery in LSD animal models with variable outcomes. In most cases, widespread CNS vector distribution was reported (19)(20)(21), with the exception of i.c.v. administration of AAV4 that resulted in the exclusive transduction of ependyma (52).…”

“…Adenoassociated virus (AAV) vector-mediated gene transfer, in particular, has shown promising results as an in vivo gene transfer tool, showing longterm production of therapeutic proteins in animal models and in humans (14)(15)(16). Extensive gene delivery to the CNS using AAV vectors has been achieved by multiple direct injections into the brain parenchyma (17,18) or by delivery to the cerebrospinal fluid (CSF) (19)(20)(21). Direct delivery of AAV vectors to the brain parenchyma is being clinically explored in MPS IIIA.…”

Therapies of mucopolysaccharidosis IVA (Morquio A syndrome)

“…Therefore, studies on gene therapy for MPS III have mainly focused on the correction of the neurodegeneration. As shown in Table 1, AAV [66,70-75], lentivirus [70,76-78] and canine adenovirus (AdV) vectors [79,80] have been evaluated for MPS IIIA and IIIB gene therapies, which have been delivered intravenously or by direct brain injection (i.e., intracranial, intraventricular, intracisternal or intracranial). A common approach for the treatment of MPS III was intravenous pretreatment with mannitol, which in most cases allowed an increase of the number of transduced cells in both brain and peripheral organs, as well as improvement of the therapeutic effect of the therapy [71,72,75,78].…”

“…As shown in Table 1, AAV [66,70-75], lentivirus [70,76-78] and canine adenovirus (AdV) vectors [79,80] have been evaluated for MPS IIIA and IIIB gene therapies, which have been delivered intravenously or by direct brain injection (i.e., intracranial, intraventricular, intracisternal or intracranial). A common approach for the treatment of MPS III was intravenous pretreatment with mannitol, which in most cases allowed an increase of the number of transduced cells in both brain and peripheral organs, as well as improvement of the therapeutic effect of the therapy [71,72,75,78]. Except for the studies carried out with canine AdV vector [79,80], gene therapy for MPS IIIA and IIIB showed long-term vector maintenance and expression, improvement in behavioral performance, reduction of GAG in urine and/or tissues, increase in life span and normalization of secondary enzymatic activities (e.g., β-glucuronidase or β-hexosaminidase).…”

Innovative Therapeutic Approaches for Improving Patient Life Condition with a Neurological Lysosomal Disease

“…More recently, a widespread enzymatic correction of CNS tissues was obtained after one single intracerebral injection of therapeutic lentiviral vector in leukodystrophy mouse models (Lattanzi et al, 2010). Several other teams have shown promising results in MPS IIIB, MPS I, MPS IIIA mouse or dog models, using either intracranial AAV-mediated gene therapy (Heldermon et al, 2010;Ellinwood et al, 2011;McIntyre et al, 2010;Fraldi et al, 2007) or intracisternal AAV gene transfer (Fu et al, 2010).…”