Intra-CSF AAV9 and AAVrh10 Administration in Nonhuman Primates: Promising Routes and Vectors for Which Neurological Diseases?

Abstract

The identification of the most efficient method for whole central nervous system targeting that is translatable to humans and the safest route of adeno-associated virus (AAV) administration is a major concern for future applications in clinics. Additionally, as many AAV serotypes were identified for gene introduction into the brain and the spinal cord, another key to human gene-therapy success is to determine the most efficient serotype. In this study, we compared lumbar intrathecal administration through catheter implantation and intracerebroventricular administration in the cynomolgus macaque. We also evaluated and compared two AAV serotypes that are currently used in clinical trials: AAV9 and AAVrh10. We demonstrated that AAV9 lumbar intrathecal delivery using a catheter achieved consistent transgene expression in the motor neurons of the spinal cord and in the neurons/glial cells of several brain regions, whereas AAV9 intracerebroventricular delivery led to a consistent transgene expression in the brain. In contrast, AAVrh10 lumbar intrathecal delivery led to rare motor neuron targeting. Finally, we found that AAV9 efficiently targets respiratory and skeletal muscles after injection into the cerebrospinal fluid (CSF), which represents an outstanding new property that can be useful for the treatment of diseases affecting both the central nervous system and muscle.

Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage accumulation

“…These approaches will not target all cell types equally. For example, studies in non-human primates have demonstrated that intravenous administration of AAV9 in juvenile non-human primates predominately transduces glia (19,33) while direct administration into the cerebral spinal fluid (CSF) improves delivery to neurons (34).…”

“…These approaches will not target all cell types equally. For example, studies in non-human primates have demonstrated that intravenous administration of AAV9 in juvenile non-human primates predominately transduces glia 21,37 while direct administration into the cerebral spinal fluid (CSF) improves delivery to neurons 38 (34). Our results suggest that maximizing neuronal correction will be essential to develop a treatment that improves functional outcomes in CLN3 disease.…”

Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies

“…While direct IP AAV delivery is highly efficient and well tolerated, it requires complex surgeries and in diseases like leukodystrophies that affect large brain areas a trade-off between surgical risk and number of injection-sites is required. Consequently, alternative delivery routes were investigated and following ICV injection, AAV8 and AAV9 were identified as the superior serotypes crossing the CBB, while AAV4 appeared favorable when exclusively targeting the ependymal cell layer ( Davidson et al, 2000 ; Chakrabarty et al, 2013 ; Bey et al, 2020 ). Comparison of 12 rAAV vectors for transgene expression in the CNS following IV revealed that particularly AAV7, AAV8, AAV9, AAV.rh8, AAV.rh10, AAV.rh39 and AAV.rh43 crossed the BBB ( Gray et al, 2013 ; Samaranch et al, 2013 ; Yang et al, 2014 ).…”

Clinical Trials for Gene Therapy in Lysosomal Diseases With CNS Involvement

“…For CNS- in vivo GT (i.e., direct introduction of the therapeutic vector into the CNS), AAVs have emerged as the safest vector and are the most commonly used ( Kantor et al, 2014 ), allowing various routes of administration, with specific targeting capacities depending on the capsid choices, stable transgene expression in postmitotic cells, low immunogenicity and low risk of toxicity or insertional mutagenesis. The vector can be delivered directly into the brain (intracerebral) or into the CSF (intrathecal, intracerebroventricular, or intracisternal) ( Bey et al, 2020 ). More recently, new serotypes of AAV have been shown to target the CNS after intravenous administration (in this case the vector has to cross the BBB), AAV9 and AAVrh10 being the most frequently used serotypes in clinical practice, due to their high capacity to transduce neural cells ( Cearley et al, 2008 ; Piguet et al, 2017 ; Bey et al, 2020 ) and some ability to cross the BBB.…”

“…The vector can be delivered directly into the brain (intracerebral) or into the CSF (intrathecal, intracerebroventricular, or intracisternal) ( Bey et al, 2020 ). More recently, new serotypes of AAV have been shown to target the CNS after intravenous administration (in this case the vector has to cross the BBB), AAV9 and AAVrh10 being the most frequently used serotypes in clinical practice, due to their high capacity to transduce neural cells ( Cearley et al, 2008 ; Piguet et al, 2017 ; Bey et al, 2020 ) and some ability to cross the BBB. More recently, new AAV serotypes have been engineered with high tropism for the CNS after intravenous administration ( Li and Samulski, 2020 ).…”