Mucopolysaccharidosis IIIB confers enhanced neonatal intracranial transduction by AAV8 but not by 5, 9 or rh10

Abstract

Sanfilippo syndrome type B (mucopolysaccharidosis IIIB, MPS IIIB) is a lysosomal storage disease resulting from deficiency of N-acetyl-glucosaminidase (NAGLU) activity. To determine the possible therapeutic utility of recombinant adeno-associated virus (rAAV) in early gene therapy-based interventions, we performed a comprehensive assessment of transduction and biodistribution profiles of four central nervous system (CNS) administered rAAV serotypes, -5, -8, -9 and -rh10. To simulate optimal earliest treatment of the disease, each rAAV serotype was injected into the CNS of neonatal MPS IIIB and control animals. We observed marked differences in biodistribution and transduction profiles between the serotypes and this differed in MPS IIIB compared with healthy control mice. Overall, in control mice, all serotypes performed comparably, although some differences were observed in certain focal areas. In MPS IIIB mice, AAV8 was more efficient than AAV5, -9 and -rh10 for gene delivery to most structures analyzed, including the cerebral cortex, hippocampus and thalamus. Noteworthy, the pattern of biodistribution within the CNS varied by serotype and genotype. Interestingly, AAV8 also produced the highest green fluorescent protein intensity levels compared with any other serotype and demonstrated improved transduction in NAGLU compared with control brains. Importantly, we also show leakage of AAV8, -9 and -rh10, but not AAV5, from CNS parenchyma to systemic organs. Overall, our data suggest that AAV8 represents the best therapeutic gene transfer vector for early intervention in MPS IIIB.

Overcoming Limitations Inherent in Sulfamidase to Improve Mucopolysaccharidosis IIIA Gene Therapy

“…The inconsistency with results obtained in MPS IIIA mice and dog studies may simply be because of size differences between mice, dog, and human brain, or other factors. Interestingly, viral uptake can be impacted by disease in LSD mice, likely because of changes in extracellular matrix components that can occur in the setting of altered degradative pathways 9, 10. Additionally, the success of cross-correction relies on effective secretion from transduced cells and distribution to non-transduced cells.…”

Site-specific modifications to AAV8 capsid yields enhanced brain transduction in the neonatal MPS IIIB mouse

“…Improved transduction of mouse skeletal muscle was also obtained with tyrosine mutants of AAV8 in the lungs [11] and in the skeletal muscle by AAV6 vectors [12]. In our previous studies, we compared neonatal intracranial administration of AAV5, −8, −9, and -rh10 and concluded that AAV8 was superior to AAV5, −9, and rh10 in its ability to foster robust and widespread transduction within the mucopolysaccharidosis type IIIB (MPS IIIB) brain [13,14]. Consistent with previous studies, we also showed that AAV8 expressed a preference for neurons and astrocytes when injected in neonates.…”

How close are we to therapies for Sanfilippo disease?

“…Even among AAV vectors, different virus serotypes may give various results when administered to organisms. Therefore, 4 AAV vectors bearing the NAGLU gene, derived from AAV5, AAV8, AAV9 and AAVrh10, were tested in MPS IIIB mouse model (Gilkes et al 2016 ). Following direct injection of the viruses into CNS, various parameters were assessed, including bio-distribution and efficiency of NAGLU transduction.…”

“…Following direct injection of the viruses into CNS, various parameters were assessed, including bio-distribution and efficiency of NAGLU transduction. Among tested vectors, AAV8 appeared the best one for treatment of MPS IIIB (Gilkes et al 2016 ). Nevertheless, one should consider that preferences in this animal model might potentially differ from those in patients suffering from Sanfilippo disesse.…”