Intracisternal delivery of AAV9 results in oligodendrocyte and motor neuron transduction in the whole central nervous system of cats

Abstract

Systemic and intracerebrospinal fluid delivery of adeno-associated virus serotype 9 (AAV9) has been shown to achieve widespread gene delivery to the central nervous system (CNS). However, after systemic injection, the neurotropism of the vector has been reported to vary according to age at injection, with greater neuronal transduction in newborns and preferential glial cell tropism in adults. This difference has not yet been reported after cerebrospinal fluid (CSF) delivery. The present study analyzed both neuronal and glial cell transduction in the CNS of cats according to age of AAV9 CSF injection. In both newborns and young cats, administration of AAV9-GFP in the cisterna magna resulted in high levels of motor neurons (MNs) transduction from the cervical (84±5%) to the lumbar (99±1%) spinal cord, demonstrating that the remarkable tropism of AAV9 for MNs is not affected by age at CSF delivery. Surprisingly, numerous oligodendrocytes were also transduced in the brain and in the spinal cord white matter of young cats, but not of neonates, indicating that (i) age of CSF delivery influences the tropism of AAV9 for glial cells and (ii) AAV9 intracisternal delivery could be relevant for both the treatment of MN and demyelinating disorders.

Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9

“…According to this study, although both administration routes generated similar distribution patterns, intra-CSF injection induced a greater CNS transduction. Furthermore, current research validated these findings in cats after intracisternal delivery [132]. This study showed that AAV9 is able to transduce the majority of MNs in the spinal cord and presents low off-target distribution both in newborn and young cats.…”

CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome)

“…There is considerable variability in the literature regarding the main CNS cell type targeted by AAV9. Several factors have been held accountable for the differences observed, including the route of delivery (73,74), the age at administration (75), the animal species (73,(76)(77)(78), the doses used, the promoter included in the expression cassette (74,79), and even the single-or double-stranded nature of the AAV (80). Alternatively, the quality of vector preparations could play an important role in determining vector tropism (81).…”

Gene therapy for Mucopolysaccharidoses

“…However, rAAV2 shows poor transduction efficiency compared with other rAAVs. Recently, it has been shown that rAAV8 and 9 are more efficiently transduced into CNS lesions after IT or IV administration [51,64,66,71–75]. In this section, we summarized recent studies of rAAV-mediated gene therapy in animal models of each type of MPS.…”