Trials to treatments: targeting alpha-synuclein
Alpha-synuclein plays an important role in Parkinson’s and researchers believe this protein can cause problems in cells. Today, there are a number of clinical trials targeting alpha-synuclein that aim to protect brain cells and slow down Parkinson’s.
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Despite decades of research we still have an incomplete understanding of this mysterious protein, alpha-synuclein. When it’s working properly, we believe it may play a role in helping brain cells to send messages to other brain cells — but it may be involved in several other activities too. But when it’s not working properly, it can cause problems inside cells.
The problem of misfolded protein
Proteins carry out all the jobs that happen inside our cells. There are lots of different types of proteins, with many different roles, such as enzymes that build and break down other molecules or hormones that help to send messages. To function properly, proteins have to be the correct shape and this depends on them folding properly. You could think of this like a paper aeroplane — when the paper is folded in a specific way it forms the correct shape needed to fly.
Misfolded proteins can clog up cells stopping them from working, so it is important that cells remove them and prevent this waste building up. But in conditions like Alzheimer’s and Parkinson’s, we know that misfolded proteins become a big problem for brain cells.
In Parkinson’s, the main protein that misfolds is alpha-synuclein and it is in the cells of a region of the brain called the substantia nigra where we see sticky clumps of protein, called Lewy bodies, forming. The misfolded alpha-synuclein causes a secondary problem, it triggers more of the protein to misfold. This adds to the build-up of waste inside cells, increasing its toxic effect and eventually leading to the loss of brain cells.
Stopping the spread of alpha-synuclein
Research has suggested that alpha-synuclein may also be important in the spread of problems from cell to cell inside the brain. Researchers have shown that toxic, misfolded alpha-synuclein can escape from brain cells and be taken into neighbouring cells, which then go on to develop problems.
But the brain isn’t the only place where the spread of toxic alpha-synuclein may be happening — recent research has also found misfolded alpha-synuclein in the gut and appendix of those in the early stages of Parkinson's. This finding has led some researchers to believe that Parkinson’s may, at least for some, start in the gut and travel to the brain. You can read more about this in our previous blog- ‘Could your gut be affecting your health?’
So, research teams are now working to develop new treatments that could halt the spread of alpha-synuclein — including vaccines, a previous blog was written on this topic:
Here we summarise compounds that are being developed to potentially interfere with the damage caused by alpha-synuclein. Targeting it could slow down Parkinson’s and may even be able to stop the clumps of alpha-synuclein from getting to the brain.
Phenylbutyrate-triglyceride (or PBT because that is impossible to say!)
Some success has been seen in the lab where this compound removes clumps of alpha-synuclein from the brain into the blood, which researchers believe could stop it having toxic effects on brain cells.
A recent trial of PBT at the University of Colorado, looked to test this theory in people. This potential drug was administered as a spoonful of liquid to 40 participants, where half were people with Parkinson’s. Their blood levels of alpha-synuclein were measured over a period of four weeks.
It was found that there was increased alpha-synuclein in the blood. This is promising because it suggests that the toxic alpha-synuclein has moved out of the brain where it is causing problems.
Now a larger and longer clinical trial is needed to assess whether this treatment is safe and beneficial to people with Parkinson’s in the long term.
NPT 200–11
Neuropore and UCB, two biotech companies, are developing another orally administered treatment that aims to stop the formation of clumps of alpha-synuclein. Hoping to reduce the toxic effect on brain cells.
NPT 200–11 has been shown to be successful in the lab and has led to early trials in people. A current phase I trial in the US will assess the safety of the drug in 55 healthy individuals.
Nilotinib and Ambroxol
Another way to target alpha-synuclein has been using drugs that were originally designed for alternative purposes. This includes drugs like Nilotinib and Ambroxol. These are currently going through phase II trials for Parkinson’s, to protect struggling brain cells. You can read more about these two drugs in our previous blog- ‘Trials to treatments- re-purposed drugs’.
ENT-01
As well as targeting alpha-synuclein in the brain, sticky clumps of alpha-synuclein can form and potentially be targeted in the gut.
The biotech company Enterin have developed ENT-01 to target the removal of alpha-synuclein from the gut. Hopefully, this will help constipation, disturbed sleep, and hallucinations.
The potential drug is based on squalamine, that naturally occurs in some species of the dogfish shark. Squalamine has been shown to have antibacterial properties and even anti-cancer effects and researchers at the University of Cambridge found that it reduced clumping of alpha-synuclein in worms.
Following on from this, a recent phase I trial in the US studied ENT-01 in 10 patients over an 8–12 week period to confirm the compound was safe. A further 40 people were enrolled in phase II trials and were studied over an 8–10 week period.
This study recorded the frequency of bowel movements alongside other non-motor symptoms. This study has been completed in the US but results are yet to be reported but we’ll be keeping an eye out for them.
Learning from Alzheimer's?
While most research has focused on alpha-synuclein. There are other proteins involved in Parkinson’s that need to fold properly in order to protect brain cells. This is also the case in Alzheimer’s.
One treatment, LMTX, targeting a misfolded protein is currently under study for Alzheimer’s but may also be relevant to Parkinson’s.
While results from clinical trials were mixed for Alzheimer's, in 2018 it was published that the active component of this treatment, LMTM, had potentially positive implications for Parkinson’s. It was shown in the lab to reduce clumps of alpha-synuclein leading to improved movement and decreased anxiety traits.
This will need to be tested in people and there have yet to be reports of a clinical trial. However, we already know a lot about the safety of this drug from the Alzheimer's trial, so this could speed up future trials.
Another compound under development is called Posiphen by QR Pharma Incorporated. This has been shown to stop the clumping of alpha-synuclein alongside other proteins, such as Tau, that also have toxic effects on brain cells.
The UCSF, University of California and San Francisco, have studied this compound in Parkinson’s models in the lab. It seems to decrease the production of alpha-synuclein which means there is less protein to clump up.
While it is currently in phase II trials for Alzheimer’s there is yet to be a clinical trial for Parkinson’s.
More to come from targeting alpha-synuclein
Targeting alpha-synuclein offers a promising way to stop the toxic effects of this protein in Parkinson’s. Researchers are looking for even more inventive ways to target it, such as using our own immune system by developing vaccines.
Before treatments are available more clinical trials are needed to test the safety and the long term benefits to people with Parkinson’s.
Will you help fund more research into alpha-synuclein and help find new treatments for Parkinson’s? Right now Professor Spillantini and her team are testing a new compound to see if it can have an effect on alpha-synuclein and in turn reduce Parkinson’s symptoms. You can support this vital work and help bring forward better treatments and a cure, and improve quality of life for everyone affected by Parkinson’s.
