Precisely opening a gate to the brain in mice

Date:
January 31, 2022
Source:
University of Maryland School of Medicine
Summary:
Researchers developed a technique in laboratory animals to
consistently and reproducibly open the blood-brain barrier. This
barrier serves as a barricade securing the brain from the external
world blocking out certain environmental toxins, but also prevents
drug therapies from reaching their intended targets. The new
technique is based on a routine procedure for removing clots from
the brain's arteries in patients. Their paper essentially provides
a roadmap for other researchers to develop and test new therapies
for brain diseases.



FULL STORY ========================================================================== University of Maryland School of Medicine researchers developed a
technique in laboratory animals to consistently and reproducibly open
the blood-brain barrier. This barrier serves as a barricade securing the
brain from the external world blocking out certain environmental toxins,
but also prevents drug therapies from reaching their intended targets. The
new technique is based on a routine procedure for removing clots from
the brain's arteries in patients. This advancement was conducted by Piotr Walczak, MD, PhD, Professor of Diagnostic Radiology and Nuclear Medicine
at the University of Maryland School of Medicine, and Miroslaw Janowski,
MD, PhD, Associate Professor of Diagnostic Radiology and Nuclear Medicine
at the University of Maryland School of Medicine.


==========================================================================
The team published their detailed procedure on December 13, 2021, in
Nature Protocols.Their paper essentially provides a roadmap for other researchers to develop and test new therapies for brain diseases. The
hope is for researchers to use this procedure for treatments against
brain cancer, neurological disorders like epilepsy, neurodegenerative
diseases like Alzheimer's and Parkinson's, or even mental illnesses. The researchers say the technique can potentially be applied in conjunction
with the latest medical discoveries, such as genome editing or gene
therapy to treat incurable cancers.

The procedure uses magnetic resonance imaging (MRI), which provides
feedback in real-time, to control where in the brain the blood-brain
barrier gate opens, allowing materials to pass through into spaces that
they are normally excluded.

"Scores of interventional radiologists worldwide navigate various
sophisticated devices in arteries for standard plumbing tasks in the
human brain, like aneurysms or strokes. If there is a leak, they fix
it. If there is a clog, they pump it out. This route could be also used
to deliver drugs, but the technique had not been perfected in mice and
other laboratory animals," said senior study author Dr. Walczak. "Since
most preclinical research starts with mice, it was essential to show
how to do this procedure properly in these animals, so scientists
across the globe will be able to use it for their drugs to get them
to the brain. Some of these drugs will ultimately land in patients as treatments benefiting society." Some scientists over the years tried to
get drugs into the brains of laboratory animals using other routes such
as injecting directly into the brain or the fluid surrounding the brain.

"Researchers had no way of knowing if the drug made it where it was
supposed to go at the time of the experiment and some researchers
found the procedure unsafe in animals," said co-author Dr. Janowski,
and co-director with Dr.

Walczak of the Program in Image-Guided Neurointerventions.

For their specific MRI-guided injection technique, the researchers
anesthetized a mouse and surgically inserted the catheter in the neck
into the carotid artery that runs to the brain (in people, they use
an artery in the groin or hand without requiring surgery). Then,
they put the mouse in the MRI machine and performed a scan, while
a pump precisely controlled injection speed. To open the blood-brain
barrier, the researchers used a solution of mannitol (a type of sugar --
a low-cost substance currently used in patients for other treatments)
that essentially sucks the liquid out of the cells in blood vessel walls, opening the seals between these cells. Before opening the barrier, they
infused gadolinium -- a contrast agent used in human medical procedures
- - through the catheter into the artery, allowing them to see whether
the injected material went to its proper destination. If the injection
did not work, they adjusted the parameters. Once the conditions were
optimized, they opened the barrier in that area of the brain. They used
this approach in several other studies targeting biotechnological drugs,
such as antibodies, to the brain. Now, the researchers hope their detailed protocol will help other researchers deliver their drug of choice to
the brains of their favorite mouse models and eventually help patients.

"Arterial procedures are typically guided using x-ray imaging methods,
and that only lets you see the map of the highways in the brain, but
these maps are not detailed enough if you needed to go beyond that to the backroads to reach the forest of the brain cells," said Dr. Janowski. "We believe that by adding MRI, we closed the gap, both in animal studies
and in the future in the clinical trials, by providing the necessary
level of precision for opening the gate to the brain for the drugs."
University of Maryland School of Medicine Dean E. Albert Reece,
MD, PhD, MBA, who is Executive Vice President for Medical Affairs
and the John Z. and Akiko K. Bowers Distinguished Professor, said,
"Perfecting basic science techniques like this one are key to laying
the groundwork to advancing treatment options for the many diseases
of the brain. Sometimes in order to advance clinical research, we have
to go back to basics first." Additional authors of the study included Post-Doctoral Fellows Chengyan Chu, MD, Yue Gao, MD, and Xiaoyan Lan,
MD; Research Associate Anna Jablonska, PhD, Yajie Liang, MD, PhD,
Assistant Professor of Diagnostic Radiology and Nuclear Medicine, and
Monica Pearl, MD, Adjunct Associate Professor of Diagnostic Radiology
and Nuclear Medicine at the University of Maryland School of Medicine;
Wojciech Lesniak, PhD, and Guanshu Liu, PhD, of Johns Hopkins Medicine;
Shen Li, MD of Dalian Municipal Central Hospital, China; and Tim Magnus,
MD, PhD of University Medical Center Hamburg-Eppendorf, Germany.

This work was funded by the Maryland Stem Cell Research Fund
(2017-MSCRFF-3942 and 2019-MSCRFF-5031) and grants from the National
Institute of Neurological Disorders and Stroke (R01NS091110, R01NS102675,
and R21NS091599).

Dr. Pearl, Dr. Janowski, and Dr. Walczak are founders and equity holders
in IntraART. Dr. Janowski and Dr. Walczak are founders and equity holders
in Ti- Com.

special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by
University_of_Maryland_School_of_Medicine. Original written by Vanessa
McMains. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Chengyan Chu, Anna Jablonska, Yue Gao, Xiaoyan Lan, Wojciech
G. Lesniak,
Yajie Liang, Guanshu Liu, Shen Li, Tim Magnus, Monica Pearl,
Miroslaw Janowski, Piotr Walczak. Hyperosmolar blood-brain barrier
opening using intra-arterial injection of hyperosmotic mannitol
in mice under real-time MRI guidance. Nature Protocols, 2021; 17
(1): 76 DOI: 10.1038/s41596-021- 00634-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220131140250.htm

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