Objective: Focal brain delivery of gene therapy in non-human primates is a major step towards the translation of this technology for use in humans. We aimed to evaluate whether systemically injected Adeno Associated Vectors (AAV) can be delivered safely, reliably, and in a controlled manner in non-human primates’ brain by combining low-intensity magnetic resonance-guided focused ultrasound (FUS) and intravenous microbubbles.

Background: Potentially promising drugs and antibody therapies for neurodegenerative disorders are often limited by their inability to efficiently cross the blood-brain barrier (BBB). Thus, gene therapy for central nervous system disorders currently requires direct injections into multiple brain regions. While FUS BBB opening has been recently used to successfully enhance antibodies or viral vectors delivery in rodents nobody has achieved to deliver any of these candidates with FUS in non-human primates.

Method: BBB in the putamen of 6 macaques (Macaca fascicularis) was opened with FUS. Low-intensity sonication were applied transcranially under MRI guidance, targeting a grid of sub-spot locations in the whole putamen structure. Microbubbles (Luminity) were delivered continuously during sonication with intravenous perfusion using an infusion pump. Treatment effects were monitored using MRI T2*, FLAIR and T1-weighted imaging with Gadolinium contrast. Following confirmation of successful BBB opening, we injected intravenously a single dose of AAV9-GFP (Green Fluorescent Protein). After one-month animals were sacrificed and detailed immunohistochemical assessment of the brains was completed.

Results: After sonication the relative gadolinium signal enhancement was significantly higher in the putamen compared to any other brain area in each monkey, indicating the successful opening of the BBB. No edema or hemorrhage was found on magnetic resonance images after BBB opening. Postmortem analysis demonstrates successful neuronal GFP expression only in the contrast-enhanced regions observed in T1-MR images from the same animals in absence of any apparent tissue damage.

Conclusion: FUS is a viable tool to deliver focally and noninvasively AAV in non-human primate brain regions. This approach may be useful to alter the progression of several neurodegenerative diseases and improve therapeutic outcomes particularly in the prodromal stages.

« Back to 2022 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/noninvasive-focal-delivery-of-adeno-associated-vectors-aav-with-magnetic-resonance-guided-focused-ultrasound-in-non-human-primates/