Key Points
- Viral gene therapies have been shown to be a promising treatment for Parkinson’s disease, but most of them cannot cross the blood-brain barrier (BBB) in therapeutically relevant doses.
- To address these issues, researchers created a novel gene therapy method and then used focused ultrasound to deliver it across the BBB in a preclinical model.
- Immunohistochemistry analyses showed that the newly inserted genes were being expressed in one of the two targeted brain regions.
Microbubble Drug Conjugate and Focused Ultrasound Blood Brain Barrier Delivery of AAV-2 SIRT-3
Gene therapies have been shown to be a promising treatment for Parkinson’s disease and other neurodegenerative disorders, but invasive, surgical delivery has impacted their efficacy. AAV9 crossed the BBB better than other serotypes, but its global delivery throughout the brain can trigger immune responses that require an immunosuppression regime. This limits AAV9’s treatable patient population.
To address these issues, James Keenan, CEO of Artenga, Inc., a Canadian life sciences company, partnered with Sunnybrook Research Institute, the University of Toronto, and the National Research Council of Canada to create a novel method to join adeno-associated virus (AAV) gene therapy with a microbubble to form a microbubble-drug conjugate (MDC), intravenously inject the entire compound, and then use focused ultrasound to deliver it across the BBB and transfect the targeted brain cells. The researchers sought to deliver the gene, which is called Sirtuin-3, to two regions of the brain affected by Parkinson’s disease: the striatum and the substantia nigra. They used AAV2, which does not trigger an immune response.
The preclinical experiments were successful. Immunohistochemistry analyses showed that the newly inserted genes were being expressed in one of the two targeted brain regions (the striatum). The research team concluded that the technology could likely be used to treat Parkinson’s disease and other neurodegenerative disorders. Furthermore, the new MDCs are clinically scalable for use in human clinical trials.
“We are reaching out to biotechnology and pharmaceutical companies developing viral gene therapies that could benefit from the focused ultrasound plus MDC noninvasive, targeted BBB delivery,” said Mr. Keenan. “In addition to higher dose and greater perfusion and retention with MDCs versus sequential administration of microbubbles and drug, there is emerging evidence that the MDC configuration also reduces the immune response and can increase the in vivo half-life of some compounds. We are very grateful to the Focused Ultrasound Foundation for their support.”
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