Nitrous Oxide Facilitates Safe Passage of Genes into the Brain, Offering Potential for Improved Gene Therapy
Nitrous oxide, a commonly used anesthetic gas, has demonstrated potential in enhancing the safety and efficacy of gene therapy delivery to the brain when combined with focused ultrasound (FUS). This breakthrough, as reported by UT Southwestern Medical Center researchers, momentarily increases the permeability of the blood-brain barrier (BBB), which is a major hindrance in delivering therapeutic agents to the brain.
The researchers found that nitrous oxide expands microbubbles, thereby reducing the required intensity of FUS to open the BBB. This innovative approach necessitates significantly lower concentrations of microbubbles and ultrasound pressure, thereby minimizing the risk of tissue damage.
In mouse models, the enhanced delivery method led to more efficient gene transfer, as evidenced by the expression of a glowing protein in targeted brain areas. These promising results offer a promising pathway for potential clinical trials aimed at treating neurological diseases more effectively and securely.
Dr. Bhavya R. Shah, Associate Professor of Radiology, Neurological Surgery, and a member of the Advanced Imaging Research Center at UT Southwestern, led the study. Deepshikha Bhardwaj, Ph.D., Senior Research Associate at UTSW, was the study's first author.
The BBB, a semipermeable border of cells lining tiny blood vessels supplying blood to the brain, is thought to have evolved to protect the brain from toxins and infections. However, it also impedes the delivery of drugs that could be used to treat neurologic or neuropsychiatric conditions.
Researchers have long sought solutions to temporarily open the BBB and allow treatments to enter. Traditional methods employ high concentrations of microbubbles and intense FUS, which pose potential risks to brain tissue.
In the new study, the researchers discovered that nitrous oxide, when administered during the BBB-opening procedure, requires up to 1,000 times lower concentrations of microbubbles and significantly lower FUS pressure compared to air. This reduction in microbubble doses and FUS pressure poses significantly less risk than conventional procedures.
As proof of principle, the researchers tested their new approach by delivering a gene that produces a glowing green protein. The results showed significantly greater uptake of the gene compared to air, as observed in a brighter glow from the targeted brain regions.
The researchers' next step will be to safely test this approach in clinical trials. Other UTSW researchers who contributed to this study include Marc Diamond, M.D., Director of the Center for Alzheimer's and Neurodegenerative Diseases and Professor of Neurology and Neuroscience; Rachel Bailey, Ph.D., Assistant Professor in the Center for Alzheimer's and Neurodegenerative Diseases and of Pediatrics; Sandi Jo Estill-Terpack, B.S., Lab Manager in the Diamond Lab; Darren Imphean, M.D., Radiology resident; and Venugopal Krishnan, Ph.D., postdoctoral researcher.
The study was funded by a UTSW High Impact Grant. For further details, readers may refer to the original research published in Gene Therapy.
- Neuroscience news highlighted a breakthrough in gene therapy delivery to the brain, as UT Southwestern Medical Center researchers found that nitrous oxide can temporarily open the blood-brain barrier (BBB) more safely and effectively.
- The experiments on mouse models demonstrated that the enhanced delivery method, which involves using nitrous oxide with focused ultrasound (FUS), led to more efficient gene transfer, as shown by the expression of a glowing protein in targeted brain areas.
- The potential benefits of this approach include the reduced risk of tissue damage, due to the lower concentrations of microbubbles and ultrasound pressure needed, as compared to traditional methods.
- The study's findings could pave the way for future clinical trials aiming to treat neurological diseases more securely and efficiently, as it addresses the challenge posed by the BBB in delivering therapeutic agents to the brain.
- As neurology, genetics, and health-and-wellness continue to advance, this innovative technique could play a significant role in the treatment of various medical-conditions related to the brain, including neurological disorders.
