Originally posted on The System Scientist.
When one thinks of a virus, notions of ‘health’ do not immediately come to mind. Historically, viruses like the common cold or the flu, and even more serious ones like HIV and Ebola, have killed millions of people around the world so it makes sense to try to avoid them. That being said, viruses have very unique properties that could be useful for drug development. However, recently researchers have adapted viral characteristics to advance a drug therapy to break amyloid plaques associated with Alzheimer’s Disease.
Destroying Plaques in Alzheimer’s
Around the world, nearly 44 million people have Alzheimer’s Disease or related dementia that afflicts 1 in 9 Americans over the age of 65. Going off of the hypothesis that this terrible disease is caused by amyloids, proteins that clump up and cause plaques in the brain, Beka Solomon of NeuroPhago Pharmaceuticals, has developed a potential therapy for destroying and preventing future plaques.
The most popular theory of Alzheimer’s Disease (AD) cause is the amyloid hypothesis. It is based on the observations that amyloid proteins, can misfold and clump together to form fibrils that cause problems in the brain. Specifically, a part of the amyloid beta precursor (APP) called amyloid-beta-peptide, can make plaques in brain tissue that lead to inflammation and loss of brain mass.
In general, there are so many factors within cellular processes that make it hard to determine what’s the main contribution to memory loss and AD, again, partially because it develops so slowly. But it is the amyloid hypothesis that might be verified via a recent drug development, inspired by a viral process.
Drug Design
Like many other successful drug therapies, the model design is inspired by natural processes. The new compound developed, NPT088, is a fusion protein (as it is made up of genetic material from different sources) is engineered to behave like a virus, M13. This virus, also called a bacteriophage because it only infects bacteria, was found to be a solid drug therapy essentially on a whim.
In 2004, Soloman was conducting an experiment using genetically altered mice, one’s that would develop AD plaques in their brain without having to wait for old age. She was testing to see if, after applying some human-made antibodies, if the beta plaques would dissolve. Generally, it is very difficult to develop a drug that can cross the blood brain barrier because the body has many mechanisms to keep foreign agents out of it’s control center, the brain. Her solution to this issue was the addition of the virus so the antibody would get into the brain. The control for this was injecting the mice with just the antibody, just the virus, and the combination of both. The results were very surprising, with just the virus having efficacy in destroying the amyloid beta plaques.
How this happened to work has to do with the cycle of M13. Initially, the phage is a single stranded DNA which the infected bacteria makes into a double stranded DNA. One of the gene products of the viral DNA is a protein that helps synthesize the foreign genetic material (in general, this is how viruses replicate in the host). M13 in particular, however, has the ability to excrete itself from the bacteria using a molecule to help it pass through the membrane. It is this peculiar attribute that lead Soloman to use it with the antibody.
At this time, there was no clear idea how a phage was dissolving the Alzheimer’s plaques, but the phage treated mice had 80% fewer plaques than untreated mice and showed signs of recovery of cognitive function.
Recent Developments
A few years after the initial findings, she, along with other researchers, actually started NeuroPhage Pharmaceuticals where they looked into more of the how and why this was happening . Richard Fisher, their first employee and biotech startup helper, had a hard time verifying that the phage dissolved the amyloid plaques when delivered via the nasal passageway, as Soloman was initially doing. However, he discovered that when injected, it could dissolve other protein aggregates like alpha-synuclein (involved in Parkinson’s) and huntingtin (Huntington’s disease). With this came a great potential for drug therapy because M13 had the ability to attack multiple targets.
The only issue was that the drug would be a live virus which is both difficult to manufacture at any large-scale and would require injection directly into the brain which is not suitable for human trials. As such, they developed a drug NPT088, that is similar to the surface proteins on M13 that dissolves the plaques. It is still very bulky and they are uncertain that it will cross the blood brain barrier, but FDA tests have shown that it’s safe in nonhuman primates and the first human trials to test for safety will start soon.
This is very exciting news, even though the logistics have not been sorted out yet. One of the overarching goals of their company, unlike their competitors, is that they are looking for other drug candidates that would, not just prevent future plaque build up, but be strong enough to break existing aggregates.
I would be interested to see if any crystallography labs will be able to capture what the surface protein bound to amyloid looks like to get a better grip on the situation. Moreover, it will be important to test if there is memory retention, or gain, with the drug. It seems there has not been much proof of cognitive recovery.
Take Away
Researchers utilizing methods that years of biological evolution has perfected is really beneficial to experiment design and drug discovery because it gives them a head start in understanding signaling pathways work in a cell. Often times with drug synthesis, it’s not until the drug reaches clinical trials that they discover some off target effects thus killing the organism being tested on and flushing years of money and funding down the drain. Instead, mimicking how bacteria and viruses work provides a way to minimize some of the undesired effects. Moreover, by copying how certain proteins function might even allow our body to process the drug better leading to achieving a healthier state sooner.
Most importantly though is the huge potential for the cure, and even prevention of serious life debilitating diseases like Alzheimer’s and Parkinson’s. So far there have only been medications that have very low efficiency at increasing, let alone maintaining, memory at older ages; and as such, this drug having very good success rates at least breaking and preventing plaque build up is very promising.
We will all have to pay close attention to the human trials to see if it is indeed a victory to ending Alzheimer’s.
Sarah Kearns is a science writer and practicing scientist of biochemistry. You can connect with her directly in the comments section and follow her on Twitter.
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Photo credit: Alzheimer’s Association