Two months ago a research report was published in the scientific journal ‘Nature’ and it caused a bit of a fuss in the embryonic stem cell world.
Embryonic stem (ES) cells are currently being pushed towards the clinic as a possible source of cells for regenerative medicine. But this new report suggested that quite a few of the embryonic stem cells being tested may be carrying genetic variations that could be bad. Bad as in cancer bad.
In this post, I will review the study and discuss what it means for cell transplantation therapy for Parkinson’s disease.
For folks in the stem cell field, the absolute go-to source for all things stem cell related is Prof Paul Knoepfler‘s blog “The Niche“. From the latest scientific research to exciting new stem cell biotech ventures (and even all of the regulatory changes being proposed in congress), Paul’s blog is a daily must read for anyone serious about stem cell research. He has his finger on the pulse and takes the whole field very, very seriously.
For a long time now, Paul has been on a personal crusade. Like many others in the field (including yours truly), he has been expressing concern about the unsavoury practices of the growing direct-to-consumer, stem cell clinic industry. You may have seen him mentioned in the media regarding this topic (such as this article).
The real concern is that while much of the field is still experimental, many stem cell clinics are making grossly unsubstantiated claims to draw in customers. From exaggerated levels of successful outcomes (100% satisfaction rate?) all the way through to talking about clinical trials that simply do not exist. The industry is badly (read: barely) regulated which is ultimately putting patients at risk (one example: three patients were left blind after undergoing an unproven stem cell treatment – click here to read more on this).
While the stem cell research field fully understands and appreciates the desperate desire of the communities affected by various degenerative conditions, there has to be regulations and strict control standards that all practitioners must abide by. And first amongst any proposed standards should be that the therapy has been proven to be effective for a particular condition in independently audited double blind, placebo controlled trials. Until such proof is provided, the sellers of such products are simply preying on the desperation of the people seeking these types of procedures.
In this post we discuss several recently published research reports suggesting that Parkinson’s disease may be an autoimmune condition. “Autoimmunity” occurs when the defence system of the body starts attacks the body itself.
This new research does not explain what causes of Parkinson’s disease, but it could explain why certain brain cells are being lost in some people with Parkinson’s disease. And such information could point us towards novel therapeutic strategies.
The first issue of Nature. Source: SimpleWikipedia
The journal Nature was first published on 4th November 1869, by Alexander MacMillan. It hoped to “provide cultivated readers with an accessible forum for reading about advances in scientific knowledge.” It has subsequently become one of the most prestigious scientific journals in the world, with an online readership of approximately 3 million unique readers per month (almost as much as we have here at the SoPD).
Each Wednesday afternoon, researchers around the world await the weekly outpouring of new research from Nature. And this week a research report was published in Nature that could be big for the world of Parkinson’s disease. Really big!
On the 21st June, this report was published:
Title: T cells from patients with Parkinson’s disease recognize α-synuclein peptides
Authors: Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A
Journal: Nature. 2017 Jun 21. doi: 10.1038/nature22815.
In their study, the investigators collected blood samples from 67 people with Parkinson’s disease and from 36 healthy patients (which were used as control samples). They then exposed the blood samples to fragments of proteins found in brain cells, including fragments of alpha synuclein – this is the protein that is so closely associated with Parkinson’s disease (it makes regular appearances on this blog).
What happened next was rather startling: the blood from the Parkinson’s patients had a strong reaction to two specific fragments of alpha synuclein, while the blood from the control subjects hardly reacted at all to these fragments.
In the image below, you will see the fragments listed along the bottom of the graph (protein fragments are labelled with combinations of alphabetical letters). The grey band on the plot indicates the two fragments that elicited a strong reaction from the blood cells – note the number of black dots (indicating PD samples) within the band, compared to the number of white dots (control samples). The numbers on the left side of the graph indicate the number of reacting cells per 100,000 blood cells.
The investigators concluded from this experiment that these alpha synuclein fragments may be acting as antigenic epitopes, which would drive immune responses in people with Parkinson’s disease and they decided to investigate this further.
There is a very interesting article in this week’s issue of Nature – one of the most eminent scientific journals.
With the 200 year anniversary of Parkinson’s disease coming up next year, the editorial team at Nature are keen to explore what is happening in the field.
There are numerous interesting articles about Parkinson’s disease available on their outlook site, but we thought this one is particularly interesting as it deals with the most controversial topic in Parkinson’s disease research.
The banner for this brief post was sourced from the HuffingtonPost
Exciting results published this week regarding a small phase 1b clinical trial of a new treatment for Alzheimer’s disease. In this post, we shall review the findings of the study and consider what they may mean for Parkinson’s disease.
An Alzheimer’s brain scans on the left, compared to a normal brain (right). Source: MedicalExpress
Alzheimer’s disease is the most common neurodegenerative disease, accounting for 60% to 70% of all cases of dementia. It is a progressive neurodegenerative condition, like Parkinson’s disease, affecting approximately 30 million people around the world.
Inside the brain, in addition to cellular loss, Alzheimer’s is characterised by the increasing presence of two features:
- Neurofibrillary tangles
- Amyloid plaques
A schematic demonstrating the difference between healthy and Alzheimer’s affected brains. Source: MmcNeuro
The tangles are aggregations of a protein called ‘Tau’ (we’ll comeback to Tau in a future post). These tangles reside within neurons initially, but as the disease progresses the tangles can be found in the space between cells – believed to be the last remains of a dying cell.
Amyloid plaques are clusters of proteins that outside the cells. A key component of the plaque is beta amyloid. Beta-amyloid is a piece of a larger protein that sits in the outer wall of nerve cells where it has certain functions. In certain circumstances, specific enzymes can cut it off and it floats away.
The releasing of Beta-Amyloid. Source: Wikimedia
Beta-amyloid is a very “sticky” protein and it has been believed that free floating beta-amyloid proteins begin sticking together, gradually building up into the large amyloid plaques. And these large plaques were considered to be involved in the neurodegenerative process of Alzheimer’s disease. Thus, for a long time scientists have attempted to reduce the amount of free-floating beta-amyloid in the brain. One of the main ways they do this is with antibodies.
What are antibodies?
An antibody is the foundation of our immune system. It is a Y-shaped structure, that is used to alert the body when a foreign or unhealthy agent is present.
An artist’s impression of a Y-shaped antibody. Source: Medimmune
Two arms off the Y-shaped antibody have what is called ‘Antigen binding sites‘. An antigen is a molecule that is capable of inducing a response from the immune system (usually a foreign agent, but it can be a sick/dying cell).
A schematic representation of an antibody. Source: Wikipedia
There are currently billions of antibodies in your body -each with specific sets of antigen binding sites – awaiting the presence of their antigen. Antibodies are present in two forms: secreted, free floating antibodies, and membrane-bound antibodies. Secreted antibodies are produced by B-cells, which are part of the immune system. And it’s this secreted form of antibody that modern science has used to produce new medicines.
Really? How does that work?
Scientists can make antibodies in the lab that target specific proteins and then inject those antibodies into a patient’s body and trick the immune system into removing that particular protein. This can be very tricky, and one has to be absolutely sure of the design of the antibody because you do not want any ‘off-target’ effects – the immune system removing a protein that looks very similar to the one you are actually targeting.
These manufactured antibodies are used in many different areas of medicine, particularly cancer (over 40 antibody preparations have been approved by the U.S. Food and Drug Administration for use in humans against cancers). Recently, large pharmaceutical companies (like Biogen) have been attempting to use these manufactured antibodies against other conditions, like Alzheimer’s disease.
Which brings us to the study published this week:
Title: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease.
Authors: Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A.
Journal: Nature. 2016 Aug 31;537(7618):50-6.
In this study, the researcher conducted a 12-month, double-blind, placebo-controlled trial of the antibody Aducanumab. This antibody specifically binds to potentially harmful beta-amyloid aggregates (both small and large). At the very start of the trial, each participants was given a brain scan which allowed the researchers to determine the baseline level of beta-amyloid in the brains of the subjects.
All together the study involved 165 people, randomly divided into five different groups: 4 groups received the 4 different concentrations of the drug (1, 3, 6 or 10 mg per kg) and 1 group which received a placebo treatment. Of these, 125 people completed the study which was 12 months long. Each month they received an injection of the respective treatment (remember these are manufactured antibodies, the body can’t make this particular antibody so it has to be repeated injected).
After 12 months of treatment, the subjects in the 3, 6 and 10 mg per kg groups exhibited a significant reduction in the levels of beta-amyloid protein in the brain (according to brain scan images), indicating that Aducanumab – the injected antibody – was doing it’s job. Individuals who received the highest doses of Aducanumab had the biggest reductions in beta-amyloid in the brain. Interestingly, this reduction in beta-amyloid in the brain was accompanied by a slowing of the clinical decline as measured by tests of dementia. Individuals treated with the placebo saw neither any reduction in their brain levels of beta amyloid nor their clinical decline.
The authors considered this study strong justification for larger phase III trials. Two of them are now in progress, with completion dates expected around 2020.
So this is a good thing right?
Yes, this is a very exciting result for the Alzheimer’s community. But the results must be taken with a grain of salt. We have discussed beta-amyloid in a previous post (Click here for that post). While it has long been considered the bad boy of the Alzheimer’s world, the function of beta-amyloid remains the subject of debate. Some researchers worry about the medical removal of it from the brain, especially if it has positive functions like anti-microbial (or disease fighting) properties.
Given that the treatment is given monthly and can thus be controlled, we can sleep easy knowing that disaster won’t befall the patients receiving the antibody. And if they continue to demonstrate a slowing/halting of the disease, it would represent a MASSIVE step forward in the neurodegenerative field. I guess what I am saying is that it is too soon to say. It will be interesting, however, to see what happens as these patients are followed up over time. And the two phase 3 clinical trials currently ongoing, which involve hundreds of participants, will provide a more definitive idea of how well the treatment is working.
So what does this have to do with Parkinson’s disease?
Yeah, so let’s get back to our area of interest: Parkinson’s disease. Biogen is the pharmaceutical company that makes the Alzheimer’s antibody (Aducanumab) discussed above. Biogen is also currently conducting a phase 1 safety trial (on normal healthy adults) of an antibody that targets the Parkinson’s disease associated protein, alpha synuclein. We are currently waiting to hear the results of that trial.
Several other companies have antibody-based approaches for Parkinson’s disease (all of them targeting the protein alpha synuclein). These companies include:
- Prothena – which completed phase 1 safety trials in March 2015 (Click here for more)
- Neuropore – which also completed phase 1 safety trials in March 2015 (Click here for more)
There are some worries regarding this approach, however. For example, alpha synuclein is highly expressed in red blood cells, and some researchers worry about what affects the antibodies may have on their function. In addition, alpha synuclein has been suspected of having anti-viral properties – reducing viruses ability to infect a cell and replicate (click here to read more on this). Thus, removal of alpha synuclein by injecting antibodies may not necessarily be a good thing for the brain’s defense system.
Unlike beta-amyloid, however, most of alpha synuclein’s activities seem to be conducted within the walls of brain cells, where antibodies can’t touch it. Thus the hope is that the only alpha synuclein being affected by the antibody treatment is the variety that is free floating around the brain.
The results of the Alzheimer’s study are a tremendous boost to the antibody approach to treating neurodegenerative diseases and it will be very interesting to watch how this plays out for Parkinson’s disease in the near future.
Watch this space!
The banner for today’s post was sourced from TheNewsHerald
It all began with a 51 year old woman named Auguste Deter.
Auguste Deter. Source: Wikipedia
She was admitted by her husband to the Institution for the Mentally Ill and for Epileptics in Frankfurt, Germany on the 25th November, 1901. Her husband complained that she suffering memory loss and having delusions.
The attending doctor was Dr Alois Alzheimer.
Over the next year, Alois continued to examine Auguste – and what he began calling the “Disease of Forgetfulness” – until he left the institute to take up a position in Munich. He made regular visits back to Frankfurt, however, to follow up on Auguste.
Auguste dies on the 8th April, 1906. She had become completely demented and had existed in a vegatative state. When he examined the brain, Alois found the hall marks of what we today call ‘Alzheimer’s disease’ (namely neurofibrillary tangles and plaques).
Now, almost 110 years later, Alzheimer’s disease is the most common neurodegenerative condition – Parkinson’s disease is the second most common. Alzheimer’s affects 850,000 people in the UK alone (Source: Alzheimer’s Society). Huge efforts have been made in researching this condition and last week some interesting new data was published about the disease that may also have implications for Parkinson’s disease.
Title: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy.
Authors: Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J, Launchbury F, Linehan J, Richard-Loendt A, Walker AS, Rudge P, Collinge J, Brandner S.
Journal: Nature. 2015 Sep 10;525(7568):247-50.
Published in the prestigious science journal, Nature, the article found signs of Alzheimer’s disease in the autopsied brains of people who had died from Creutzfeldt-Jakob disease (CJD) – the prion induced neurodegenerative condition.
What’s a prion?
Good question! A prion is a small infectious particle – usually composed of an abnormally-folded version of a normal bodily protein – that causes progressive neurodegenerative conditions. The first prion discovered in mammals was Prion protein (PRP): this is the prion that causes CJD.
PrP is considered the only known prion in mammals, but recently other proteins have exhibited prion-like behaviour. One such protein is Amyloid-β protein – the protein that is found clustered in clumps in the brains of people with Alzheimer’s disease.
The brains that were analysed in the study from the journal Nature were collected at death from people who had received human growth-hormone earlier in their lives. The growth-hormone had been extracted from human cadavers and it was injected into people with growth problems (this was a common practise during the 1950s to mid 1980s). Unfortunately, some of the growth-hormone appears to have been contaminated with PrP (possibly one of the cadavers used had undiagnosed CJD) and numerous people were injected with it (65 cases in Britain alone). Many of these individuals have been followed and we have learned a great deal from them regarding CJD. Some of these individuals have also donated their brains to science and it was some of these brains that were analysed in the study being discussed here.
What the authors of the study were expecting to see when they analysed these brains was lots of clusters of PrP. What the authors were not expecting to see was the clustering of Amyloid-β protein in these brains.
Amyloid-β protein (brown) in a section of brain tissue. Source: Nature
Of the eight brains (from people who received PrP infected growth-hormone) the authors analysed, six of them had clustering of Amyloid-β protein present in the brain (in four of those cases it was wide-spread). These brains came from people aged between aged 36–51 years – in such cases it is very rare to see large accumulations of Amyloid-β protein. The researchers also analysed the DNA of the individuals involved in the study and found that none of them were genetically susceptible to Alzheimer’s disease.
The researchers then compared these six brain with the brains of people who died from CJD caused by other means – 119 brains in total and none of them had Amyloid-β protein present in the brain. From these and other experiments, the authors suggested that this was the first human evidence of transmission of Alzheimer’s related pathology.
It is very important to note several details in the study:
1. None of the people whose brains were used in the study exhibited the clinical signs of Alzheimer’s.
2. None of the brains with Amyloid-β pathology had what is called ‘hyperphosphorylated tau neurofibrillary tangles’ – SImilar clumps of Amyloid-β protein, tau neurofibrillary tangles are another characteristic feature of Alzheimer’s disease brains. Their absence is curious.
3. The authors can not dismiss the possibility that the Amyloid-β was not present in the growth-hormone solution. In this case, the Amyloid-β accumulation in the brains could have been caused by some other unknown agent that was present in the injected solution.
A rare editorial note here: The Science of PD is disappointed with the way that this study has been handled by the wider media. While the results are interesting and the authors can be congratulated on their work, a correct interpretation of the results requires further study. This study has simply demonstrated was that Amyloid-β protein may be transmissible in a similar fashion to PrP.
So why are we discussing this Alzheimer’s research here at the Science of Parkinson’s Disease?
Well, for a long time now Parkinson’s researchers have suspected that similar mechanisms may underlying what is happening in PD. That is to say, a prion-like protein may be transmitted between cells in the body (possibly from the gut to the brain – see previous posts) allowing the disease to progress. One protein in particular, Alpha Synuclein, which is present in Lewy bodies – the neurological features associated with Parkinson’s disease, has been implicated in this regards. Recent evidence from lab-based studies suggest that this is possible in cell cultures and in rodents, but whether it is possible in humans is yet to be determined.
NOTE: Since publishing this post, we contacted the authors of the study regarding the presence of Alpha Synuclein and they told us that they were currently conducted a large study investigating what other proteins are also present. Thus far they have not seen any Alpha Synuclein accumulation. Interesting….