Overcome the blood-brain barrier: details
A new method of targeted drug delivery in Alzheimer's disease
LifeSciencesToday to the materials of the University of Oxford:
New method delivers Alzheimer’s drug to the brain
Oxford University scientists have developed a new method of delivering complex drugs directly to the brain – a necessary step in the development of treatments for Alzheimer's and Parkinson's diseases, motor neuron disease and muscular dystrophy.
These diseases have provided worthy resistance to all attempts made over the past 50 years to develop new drugs that can slow or stop their development, which is largely due to the complexity of drug delivery to the brain.
Scientists have successfully disabled a gene involved in the development of Alzheimer's disease in the brains of mice, using exosomes – the smallest particles naturally secreted by cells. Exosomes injected into the blood are able to transfer the drug to the brain through the usually impenetrable blood-brain barrier.
The exosomes shown in this electron micrograph are the smallest capsules produced by most cells of the body in various quantities. These natural nanoparticles are considered one of the means of intercellular communication and interaction of cells with the body's immune system. Breaking away from the outer walls of cells, exosomes can carry various cellular signals and genetic information.
Although the results are significant and promising, a number of steps must be taken before this new form of drug delivery can be tested in humans in a clinical setting. The study, partially funded by the Muscular Dystrophy Campaign, is published in the journal Nature Biotechnology (Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes).
"These are serious and impressive results. For the first time, a new "biological" drug has been effectively delivered through the blood–brain barrier to the brain," comments her supervisor Dr. Matthew Wood (Department of Physiology, Anatomy and Genetics, Oxford University).
Recently, a number of drugs have been developed based on antibodies, peptides and RNA molecules and focused on certain aspects of diseases. However, while showing good results in the laboratory, they cannot manifest themselves in clinical conditions due to the impossibility of their delivery to the right tissue of the body.
Currently, the delivery of any drug of this type to the brain requires the involvement of neurosurgery. Nothing that is injected intravenously will be able to get from the blood to the brain.
"The main obstacle to the use of such drugs is their delivery," explains Dr. Wood. This problem is even more complicated when it comes to the delivery of drugs to the brain, since the blood-brain barrier delays most of the substances in the blood.
Scientists from Oxford decided to adapt natural exosomes for the delivery of gene therapeutics. They used an RNA sequence that turns off a gene implicated in Alzheimer's disease.
"This is the first time this natural system has been used to deliver drugs," says Dr. Wood.
In order for the method to work, you need to load exosomes with a drug – RNA molecules. But in addition, exosomes should be oriented to the target tissues of the body.
First of all, scientists obtained and purified exosomes from mouse cells. Then they developed and patented new methods for introducing RNA molecules into exosomes and adding protein elements to their shell, allowing nanoparticles to target nerve cells.
The exosomes injected into the blood of mice crossed the blood-brain barrier and entered the brain. While there, the RNAs were able to turn off the gene involved in the formation of the "wrong" protein characteristic of Alzheimer's disease. This led to a 60 percent reduction in the level of the problematic enzyme encoded by this gene.
To realize the therapeutic potential of RNA-based drugs, effective, tissue-specific and non-immunogenic methods of their delivery should be developed. Exosomes are endogenous nanovesicles carrying RNA and protein molecules that can deliver short interfering (si) RNAs to the brains of mice. To reduce immunogenicity, mice's own dendritic cells were used to produce exosomes. Targeting was achieved by engineering dendritic cells aimed at the expression of Lamp2b, an exosome membrane protein fused with a neuron-specific RVG peptide. Purified exosomes were loaded with exogenous siRNAs by electroporation. Intravenously injected RVG-oriented exosomes delivered GAPDH siRNA to neurons, microglia, and oligodendrocytes of the brain, leading to a specific gene knockout. In wild–type mice, the therapeutic potential of siRNA delivery using exosomes was demonstrated by a significant decrease in the production of mRNA (60%) and protein (62%) of BACE1, the therapeutic target for Alzheimer's disease. (From the abstract to the article). (Picture: nature.com )
"We have shown that the natural system can be used to deliver drugs across the blood–brain barrier," Dr. Wood comments on the results. "We believe that this technology can be used to treat Alzheimer's, Parkinson's, Huntington's and motor neuron disease. All you need is different RNAs."
The next stage of the work will be to test exosomes on a mouse model of Alzheimer's disease in order to find out whether their introduction affects the development of the disease.
Before conducting clinical trials of exosomes on humans, it is necessary to conduct tests for their safety and find optimal doses and administration schemes.
Over the past 50 years, scientists have become convinced that none of these diseases can be cured with standard drugs.
"New drugs have been developed based on complex biological molecules – antibodies, peptides and RNA, but they all require new delivery methods," Dr. Wood concludes. "These natural nanoparticles will be administered intravenously, and possibly orally, and, nevertheless, will reach the brain."
Portal "Eternal youth" http://vechnayamolodost.ru25.03.2011