The Elusive Cure: How Understanding the Blood-Brain Barrier Could Lead to Cure for Alzheimer's
Over 100 years after the discovery of Alzheimer’s, there are still no treatments available to cure, slow down, or prevent the disease. There have been countless clinical trials for Alzheimer’s treatments throughout the years without any significant successes. Why is this? Are the drugs being tested not effective? Maybe, but maybe not. It’s possible that researchers have already developed a successful drug, but that they have not found a way to successfully deliver it to the brain. This lack of research into proper brain drug delivery could also be contributing to the relative underfunding of Alzheimer’s research compared to other chronic conditions. The blood-brain barrier is a highly selective border of endothelial cells that prevents solutes in circulating blood from non-selectively crossing into the area of the central nervous system where neurons are. The border is semipermeable, which means that it does let some things through, such as nutrients, ions, organic anions, glucose, water, and amino acids, while restricting the passage of pathogens and other things that can harm the brain. The blood-brain barrier makes it difficult to deliver diagnostic and therapeutic agents to the brain, which means that adequate quantities of molecules and antibodies that may be effective in diagnosis and therapy aren’t always able to cross the blood-brain barrier. Because of this, infections of the brain are difficult to treat. Antibodies are too large to cross the blood-brain barrier and only certain antibiotics can pass. Most Alzheimer’s drug candidates do not cross the blood-brain barrier, which means they can’t be properly delivered to the brain. Some evidence indicates that disruption of the blood-brain barrier in Alzheimer's disease allows amyloid beta to enter the brain, suggesting that Alzheimer’s is aggravated, and potentially even caused, by a breakdown in the blood-brain barrier.
Drugs can be composed of large or small molecules. Large molecules are unable to cross the blood-brain barrier, and over 98% of small molecules can’t cross either. It is possible to attach a drug to a Trojan horse molecule that can pass the blood-brain barrier to “sneak” the drug across, however, this method still lacks sufficient research and will require additional development before being used for drug delivery. The inability of drugs to pass through the blood-brain barrier is a major reason that less than half of all drugs that are designed to go to the brain pass clinical trials. The blood-brain barrier can’t be replicated in mice or rats, so there is no way to test that the drug will even make it through the brain-blood barrier before a clinical trial, which means that many drugs are developed that aren’t even capable of making it to the brain. Developing drugs to pass through the blood-brain barrier takes on average one year compared to other drugs.
Currently, over 99% of Alzheimer's drug development efforts are devoted to drug discovery, leaving less than 1% devoted to delivering the drug to the brain. Incorporating blood-brain barrier sciences in the discovery phase at the beginning of drug development may lead to better outcomes than the current status quo. This can be achieved by reallocating a portion of the 99% of resources that are currently used for drug discovery to drug delivery efforts. Generally, there also needs to be a better understanding of brain-blood barrier biology and brain drug targeting technology. We still seem to be a long way off on this, considering no Big Pharma company in the world today has a blood-brain barrier drug targeting program. Even if these companies wanted to start a blood-brain barrier drug targeting program, there are not enough experts on the blood-brain barrier to hire because no academic neuroscience program in the United States emphasizes blood-brain barrier transport biology. UCLA researcher William M. Pardridge, a Distinguished Professor Emeritus and blood-brain barrier expert, cites decades of under-development of blood-brain barrier drug targeting technology as a major cause of clinical trial drug failures in brain disorders. Clinical trials are often performed on drugs that don’t cross the blood-brain barrier, and when the trial fails, it is simply assumed that the drug doesn’t work without considering that it wasn’t delivered to the brain. Even when the blood-brain barrier is considered, there has typically not been a targeting technology co-developed (remember, only 1% of effort was devoted to delivery in development), so the drug still can’t be administered properly. When considering this, a drug that could successfully treat Alzheimer’s and improve quality of life may have already been discovered, but it wasn’t delivered to the brain properly and ended up being disregarded along with other unsuccessful clinical trials. Some people believe that the issue of the blood-brain barrier is the source of the underfunding challenges for Alzheimer’s research. They believe that there will be an increase in funding once this problem is solved. In a way, this stance does make sense. It doesn’t matter how many drugs you can develop or how great they are if they aren’t able to be delivered to the brain. From the perspective of the organization providing the funds, it doesn’t make sense to invest huge sums of money into developing a drug that can’t be delivered properly. It’s possible that a better understanding of the blood-brain barrier is a prerequisite for Alzheimer’s research receiving funding comparable to conditions like cancer.