Beyond the barrier: ultrasound allows AAV vectors into the brain

Researchers have successfully utilized low-intensity ultrasound to temporarily open the blood-brain barrier and deliver gene therapy directly to the brain as part of efforts to find a cure for Parkinson’s disease.

Parkinson’s disease is a neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the substantia nigra of the brain, resulting in uncontrollable movement and difficulty with coordination and balance. Current therapeutic approaches for Parkinson’s disease are aimed at alleviating symptoms rather than curing the disease.

Curative approaches for Parkinson’s disease, such as gene therapy and immunotherapy, have been limited by the difficulty in overcoming the highly selective blood-brain barrier. While invasive methods such as intracerebroventricular injections are available, these methods are associated with increased risk to patients, prompting a team of researchers led by José Obeso from CEU San Pablo University (Madrid, Spain) to seek alternative non-invasive methods.

As part of efforts to find an approach that can either stop or slow down the progression of the disease, researchers have turned to low-intensity focused ultrasound (LIFU), a non-invasive technique that has recently been shown to transiently open the blood-brain barrier. The recent study published in Science Advances describes how the team successfully employed LIFU to open the blood-brain barrier for 24-hours in six adult macaque monkeys. Following the opening of the blood-brain barrier, the team systemically administered AAV9 vectors encoding green fluorescent protein, which successfully reached the basal ganglia of the brain.

Four weeks after the delivery of the AAV9 vectors, postmortem histological analysis showed that the vector had been delivered to the targeted region in five of the macaque monkeys. Vector-induced expression of green fluorescent protein was observed in three of the five monkeys that did not have AAV9-neutralizing antibodies, which is an absence observed in half of the human population.

“Our ultimate goal is to treat neurological diseases, such as Parkinson’s, early and non-invasively,” says José Obeso, lead author of the study.

Additionally, the team reported findings from a proof-of-concept Phase 1 clinical trial conducted with three Parkinson’s patients to assess the safety and feasibility of utilizing LIFU to open the blood-brain barrier. The study described how the patients underwent 18F-choline PET imaging following the opening of the barrier with LIFU. 18F-choline is a radioactive molecule that cannot penetrate the blood-brain barrier. Blood-brain barrier openings were successfully demonstrated in the patients with the uptake of 18F-choline observed in targeted brain regions.

It is hoped that the findings from this study might offer a non-invasive approach for viral vector delivery of gene therapy for neurodegenerative disorders.

visit: neurology.pencis.com

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