Summary: Researchers have discovered that nitrous oxide can safely enhance the delivery of gene therapy to the brain by making the blood-brain barrier (BBB) more permeable when paired with focused ultrasound (FUS). This method required significantly lower concentrations of microbubbles and ultrasound pressure than conventional techniques, reducing the risk of tissue damage.
In mouse models, this approach resulted in more efficient gene delivery, as shown by the expression of a glowing protein in targeted brain areas. These promising results pave the way for potential clinical trials aimed at treating neurological diseases more effectively and safely.
Key Facts:
- Nitrous Oxide Role: Nitrous oxide expanded microbubbles, reducing FUS pressure needed to open the BBB.
- Enhanced Safety: The new technique required up to 1,000x fewer microbubbles, minimizing tissue risk.
- Effective Delivery: Gene therapy uptake in brain regions was significantly improved in mouse models.
Source: UT Southwestern
Nitrous oxide, a commonly used analgesic gas, temporarily improved the opening of the blood-brain barrier (BBB) to allow gene therapy delivery in mouse models using focused ultrasound (FUS), UT Southwestern Medical Center researchers report in a new study.
Their findings, published in Gene Therapy, could eventually lead to new ways to treat a variety of brain diseases and disorders.
“The approach we explored in this study has the potential to advance care for diseases of the brain that can be treated by targeted therapeutic delivery,” said study leader Bhavya R. Shah, M.D., Associate Professor of Radiology, Neurological Surgery, and in the Advanced Imaging Research Center at UT Southwestern.
He’s also an Investigator in the Peter O’Donnell Jr. Brain Institute and a member of the Center for Alzheimer’s and Neurodegenerative Diseases. Deepshikha Bhardwaj, Ph.D., Senior Research Associate at UTSW, was the study’s first author.
The BBB is a highly selective border of semipermeable cells that line tiny blood vessels supplying blood to the brain. It is thought to have developed during evolution to protect the brain from toxins and infections in the blood.
However, the BBB also impedes the delivery of drugs that could be used to treat neurologic or neuropsychiatric conditions, such as Alzheimer’s disease, multiple sclerosis, or brain tumors.
Consequently, researchers have worked for decades to develop solutions that can temporarily open the BBB to allow treatments to enter.
Recently, scientists discovered they could open the BBB in targeted brain areas by intravenously delivering a solution containing microscopic bubbles (microbubbles), then exposing targeted brain regions to FUS.
This causes the microbubbles to oscillate, which temporarily increases the permeability of the BBB. However, the concentrations of microbubbles and FUS pressure necessary to open the BBB can pose potential risk to brain tissue.
In the new study, Drs. Shah and Bhardwaj and their colleagues tested a novel approach that significantly reduced the microbubble concentrations and FUS pressure needed to temporarily open the BBB.
In mouse models, the researchers tested nitrous oxide, rather than medical air, during the BBB-opening procedure. Nitrous oxide is known to expand microbubbles made of other gases.
Their experiments showed that nitrous oxide required up to 1,000 times lower concentrations of microbubbles and significantly lower FUS pressure to open the BBB compared with air. Lower microbubble doses and FUS pressure posed significantly less risk than the standard procedure.
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 than when breathing air, seen 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.
Funding: This study was funded by a UTSW High Impact Grant.
About this neuroscience research news
Author: Bhavya R. Shah
Source: UT Southwestern
Contact: Bhavya R. Shah – UT Southwestern
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Nitrous oxide enhances MR-guided focused ultrasound delivery of gene therapy to the murine hippocampus” by Bhavya R. Shah et al. Gene Therapy
Abstract
Nitrous oxide enhances MR-guided focused ultrasound delivery of gene therapy to the murine hippocampus
Transcranial Magnetic Resonance Guided Focused Ultrasound can oscillate intravenously delivered microbubbles and transiently open the blood brain barrier (BBB) in a targeted brain region.
However, high microbubble doses or Focused ultrasound pressures (FUS) leads to injury. So, we administered nitrous oxide (N2O), an anesthetic gas to determine reduced need of FUS pressure and microbubble dose for opening BBB.
Swiss Webster mice were treated with N2O or medical air (MA) at varying FUS pressures, while the microbubble dose was kept constant and the vice-versa.
Consequently, BBB opening was quantified by acoustic emissions and enhancement rate on T1-weighted MR.
To compare the effect of N2O on gene delivery, following BBB opening with either MA or N2O, a viral vector expressing GFP was subsequently delivered.
Additionally, Immunohistochemical studies quantified viral transfection efficacy and assessed acute cell injury.
We observed that N2O significantly potentiates acoustic emissions and enhancement rate on post-contrast MRI images, compared to MA at all measured pressures (0.39, 0.45, 0.67 MPa).
Furthermore, N2O reduces the microbubble dose to 0.02μl/kg and FUS pressures to 0.28 and 0.39 MPa for BBB disruption and enhanced viral gene delivery, respectively.
Hence, N2O potentiates microbubble oscillations, allowing reduced microbubble dose and FUS pressures and improved viral gene delivery.
