A non-invasive method for controlled opening of the blood-brain barrier may inject drugs into the brain and thus treat diseases including Alzheimer's, Parkinson's, ALS and brain tumors
The brain is separated from the blood vessels by the blood-brain barrier (Blood-Brain Barrier - BBB). This barrier isolates the brain from the rest of the body and thus prevents pathogens (disease-causing agents) and various substances from entering it. But with all the advantages inherent in it, this barrier is also one of the main obstacles in the development of effective treatments for brain diseases, since it makes it difficult to introduce medicinal substances into the brain.
The research of Prof. Yael Mardor, Dr. Shirley Sharvi, Dr. Itzik Cooper, Dr. David Lest and PhD student Yael Bresler - from the Center for Advanced Technologies and the Yosef Segol Center for Neuroscience at the Sheba Medical Center - focuses on an effective and safe breach of the barrier in favor of Treatments for brain diseases. They are studying molecular and cellular mechanisms of action of the barrier and hope that in this way they will be able to develop methods that will overcome it and help drugs to penetrate through it.
In one of their previous studies, supported by a grant from the National Science Foundation, they examined treatment of brain tumors using electroporation; In this method, a high-intensity electric field (hundreds or thousands of volts per centimeter) creates nanometer holes in the barrier through which drugs can be injected (they then close by themselves). Using this electric field it is also possible to damage cancerous cell membranes in the brain, thus destroying malignant tumors. However, to induce a high electric field in the brain, the skull must be opened and electrodes inserted into it. That is, it is an invasive method that may cause complications (such as damage to brain tissue, bleeding and infections).
Therefore, in another study, also supported by the National Science Foundation, Mardor, Sharvi and Cooper decided to find a way to open the barrier - without opening the skull. Already at the end of their previous research they examined the difference between a high and a low electric field. They realized that the low field could also create significant physiological effects and that it might be possible to treat degenerative diseases of the brain, such as Parkinson's, Alzheimer's and the muscular dystrophy disease ALS. According to Prof. Mardor, "currently there are no effective treatments for these diseases, mainly because of the barrier. If we can find a method in which a helmet is placed on the patient's head that activates an electric field - so that the barrier opens and drugs (including those taken orally) penetrate through - we will make a big change in neurology. The realization that the barrier can be opened using a low electric field - much less than hundreds or thousands of volts - may be a breakthrough."
Therefore, the researchers wanted to create a gentle and reversible opening of the barrier, so that it would be possible, through it, to inject drugs into the brain without leaving it open for too long and damaging its function. To this end, they built a model of the barrier from human stem cells and applied an electric field to it at a strength of 50-5 volts per centimeter, using two electrodes attached to its sides. They discovered that with such a treatment, which lasts only ten seconds, it is possible to achieve a significant opening of the barrier. These are ten pulses that are given once a second; Each pulse increases the strength of the opening of the barrier and lasts 50 microseconds). The researchers tested the passage of molecules of different sizes through the barrier and found that they were able to flow through it. The transfer of molecular structures with large molecular weights (including antibodies), which currently have no way to be transferred to the brain, was also tested. As they increased the number of pulses, more and more molecules were able to pass through the barrier. That is, it is possible to control the opening strength of the barrier even when the electric field is low, and it is possible to activate it repeatedly.
In the next step, the researchers injected the mice with gadolinium (a contrast agent used in imaging tests) and attached electrodes to their heads that emitted pulses of a low electric field (similar to the one applied to the model), for a minute or two. After that, they had brain imaging and saw that the contrast material had flowed into the brain. Later they injected a dye (large molecules) into them, and showed that even large molecules were able to penetrate through the barrier with a very short treatment. Today, the researchers continue to investigate the method and the possibility of developing electrodes that would be suitable for non-invasive treatment in humans.
Life itself:
Prof. Yael Mardor, 57, is a nuclear physicist, divorced and mother of two children, 28 and 24. She decided to focus on brain tumor research and imaging following multiple cancer cases in her family. In her free time she enjoys dancing and walking in the sea.
Dr. Yitzhak Cooper, 44 years old, is the head of the blood-brain barrier group at the Segol Neuroscience Center at the Sheba Medical Center. He is married to a scientist and the father of three children, aged 12, 10 and 6. In the past he was a food engineer and among other things developed flavors for the Yopla company. Today, when he is not engaged in science, he plays tennis for fun.
Dr. Shirley Sharvi, 42 years old, married to her partner from the army and they have three children, ages 14, 11 and 5. She started her career as an electrical engineer and worked in high-tech. She then studied physical therapy and worked in neurological rehabilitation. She finally arrived at Prof. Mardor's laboratory and went through a direct path to a doctorate in medical sciences. Today she is a senior researcher and understands that this is her calling. In her spare time she likes to take pictures.
Dr. David Lest, 46 years old, married and father of three children aged 13, 11 and 5, immigrated from France in 2006. He did a doctorate and post-doctorate in brain imaging at the University of Paris-Scilla and Harvard University, and is currently a senior researcher at the Center for Advanced Technologies at the Sheba Medical Center and an expert in image processing. In his spare time he likes to ride a bicycle.
Yael Bresler, 39 years old, has a master's degree in physical therapy from Ben-Gurion University, is married and the mother of two children, 3 and a half years old. She began her career as a rehabilitation physiotherapist and for the past four years has been working on her doctorate in medical sciences at Tel Aviv University. In her spare time she enjoys reading, traveling and sailing with her family.
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