ABSTRACT: Researchers have discovered that nitrous oxide can safely improve the supply of gene therapy to the brain by making the blood brain barrier (BBB) more permeable when combined with focused ultrasound (FUS). This method required significantly lower concentrations of microburbujas and ultrasound pressure than conventional techniques, reducing the risk of tissue damage.
In mice models, this approach resulted in a more efficient gene supply, as evidenced by the expression of a brilliant protein in specific brain areas. These promising results are paving the way for possible clinical trials aimed at treating neurological diseases more effectively and safely.
Key facts:
Nitrous oxide folo: Expanded microburbujas of nitrous oxide, reducing the necessary fus pressure to open the BBB. Improved security: the new technique required up to 1,000 times less microburbujas, minimizing the risk of tissue. Effective delivery: absorption of gene therapy in the 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 the supply of gene therapy in mice models using focused ultrasound (FUS), researchers at the UT Southwestern Medical Center report on a new study.
His findings, published in Gene Therapy, could eventually lead to new ways of treating a variety of diseases and brain disorders.
“The approach we explore in this study has the potential to advance in brain diseases that can be treated by directed therapeutic delivery,” said study leader Bhavya R. Shah, MD, associate professor of radiology, neurological surgery and in the center of advanced image research in UT Southwestern.
He is also a researcher at the Peter O’Donnell Jr. Brain Institute and a member of the Alzheimer’s center and neurodegenerative diseases. Deepshikha Bhardwaj, Ph.D., Senior Research Associate in UTSW, was the first author of the study.
BBB is a highly selective edge of semipermeable cells that border small blood vessels that supply blood to the brain. It is believed that it was developed during evolution to protect the brain from toxins and blood infections.
However, BBB also prevents the administration of medications that could be used to treat neurological 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 that they could open BBB in specific brain areas by intravenously administering a solution that contains microscopic bubbles (microburbujas), then exposing specific brain regions to FUS.
This causes microburbujas to oscillate, which temporarily increases the permeability of BBB. However, microburbujas concentrations and the FUS pressure necessary to open BBB can represent a potential risk for brain tissue.
In the new study, the Drs. Shah and Bhardwaj and his colleagues tested a novel approach that significantly reduced the concentrations of microbobble and the fus pressure necessary to temporarily open the BBB.
In mice models, researchers tested nitrous oxide, instead of medical air, during the BBB opening procedure. It is known that nitrous oxide expands microburbujas made of other gases.
Their experiments showed that nitrous oxide required up to 1,000 times lower microburbujas concentrations and significantly lower fus pressure to open the BBB compared to the air. The lowest microburbujas doses and the FUS pressure raised significantly less risk than the standard procedure.
As proof of principle, the researchers tested their new approach when delivering a gene that produces a bright green protein. The results showed a significantly greater absorption of the gene than when air breathing, seen in a brighter brightness of the specific brain regions.
The next step of the researchers will be to try this approach safely in clinical trials.
Other UTSW researchers who contributed to this study include Marc Diamond, MD, director of the Alzheimer’s and neurodegenerative disease center and neurology and neuroscience professor; Rachel Bailey, Ph.D., assistant professor at the Alzheimer’s center and neurodegenerative and pediatrics; Sandi Jo Estill-Terpack, BS, Laboratory Manager in the Diamond Laboratory; Darren Imphean, MD, resident of Radiology; and Venuge Krishnan, Ph.D., postdoctoral researcher.
Financing: This study was financed by a high impact subsidy of UTSW.
On this neuroscience research news
Author: Bhavya R. Shah
Source: UT Southwestern
Contact: Bhavya R. Shah – UT Southwestern
Image: The image is accredited to Neuroscience News
Original research: closed access.
“The nitrous oxide improves the ultrasound supply focused on MR of gene therapy to the Murino hippocampus” by Bhavya R. Shah et al. Gene therapy
Abstract
Nitrous oxide improves the ultrasound supply focused on MR of gene therapy to Murino hippocampus
Ultrasound focused on transcranial magnetic resonance can range microburbujas administered intravenously and temporarily open the blood barrier (BBB) in a directed brain region.
However, the high doses of microbobble or ultrasound pressures focused (fus) lead to an injury. Therefore, we administer nitrous oxide (N2O), an anesthetic gas to determine the reduced need for the fus pressure and the microbobble dose to open BBB.
The Swiss Webster mice were treated with N2O or medical air (MA) to variable fus pressures, while the microbobble dose remained constant and the vice versa.
Consequently, the BBB opening was quantified by acoustic emissions and the improvement rate in the MR weighted by T1.
To compare the N2O effect on gene delivery, after the opening of BBB with MA or N2O, a viral vector that expresses GFP was delivered.
In addition, immunohistochemical studies quantified the effectiveness of viral transfection and evaluated acute cell lesion.
We observe that N2O significantly power of acoustic emissions and the improvement rate in magnetic resonance images after contrast, compared to MA in all measured pressures (0.39, 0.45, 0.67 MPa).
In addition, N2O reduces the dose of microbobble to 0.02 μl/kg and fus pressures to 0.28 and 0.39 MPa for the interruption of BBB and the delivery of improved viral genes, respectively.
Therefore, N2O enhances microburbujas oscillations, allowing a dose of reduced microbubujas and fus pressures and a supply of improved viral genes.
