Category: Uncategorized

A brave new world: 21st Century Cures Act

~ Simon ~ 4 Comments

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In one of his last acts as President, this week Barrack Obama signed into law the 21st Century Cures Act. Enacted by the 114th United States Congress, the new law will have enormous implications for the American health system and for the Parkinson’s community.

In today’s post we’ll review the new law and what it will mean for Parkinson’s disease.

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An early version of the hypocratic oath. Source: Wikipedia

It may surprise you, but contrary to popular belief the phrase “First do no harm” (Latin: Primum non nocere) does not appear in the Hippocratic oath that medical practitioners are suppose to abide to.

Not now, nor in the original form.

The closest we get to it is (Greek) noxamvero et maleficium propulsabo (“I will utterly reject harm and mischief”). Despite this, the basic idea of ‘not doing harm’ has been part of the foundation of medical practise since the oath was first written around the 3rd century BCE.

The idea of ‘doing no harm’, however, presents a double-edge sword for practitioners when they are faced with patients prepared to try anything to cure themselves of a crippling condition. Does the practitioner knowingly consent to allowing a subject to take a treatment that could have negative side-effects or no effect at all?

The example above is provided simply to set the stage for the discussion below. For we are about to embark on a new age when practitioners will potentially be faced with this dilemma on an ever more frequent basis.

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The United States Capitol. Source: SpotHeroBlog

The ‘Science of Parkinson’s’ is politically neutral.

We do, however, investigate proposals and new legislations that will affect the Parkinson’s community, particularly those affecting the research world.

With that said, on the 13th December 2017, President Barrack Obama signed into law one of the most sweeping efforts to provide additional support and funding for health conditions that we have seen for some time. The 21st Century Cures Act (catchy name huh?) is going to have a big impact.

What is in the new law?

The law focuses on cancer, Alzheimer’s disease, opioid addiction, medical devices, access to new drugs, and mental health.

The new law provides $4.8 billion for three of the Obama administration’s key research programs over the next 10 years: Vice President Joe Biden’s cancer moonshot, the BRAIN Initiative, and the Precision Medicine Initiative. It will also give states $1 billion to fight the opioid crisis currently affecting certain areas of the country, and deliver an additional $500 million to the Food and Drug Administration (FDA).

In addition, the ‘Cures’ law will create new databases that will access health records and allow for a greater collection of information focused on certain diseases. Of particular interest to us is the creation of the ‘National Neurological Conditions Surveillance System’ at the Centers for Disease Control and Prevention (CDC), which will collect demographic information on people living with neurological diseases, like Parkinson’s disease.

Critically, the ‘Cures’ law will speed up the regulatory process for getting new treatments and devices approved for the clinic. Currently it can take up to a decade and a billion dollars to get new drugs from the lab bench to the clinic. Patient groups have been lobbying hard for this and they will be very happy with the Act being passed into law.

Who benefits from this new law?

With every new law there are winners and losers:

Winners:

1. Pharmaceutical and Medical Device Companies. The law will give the FDA new authority to request fewer studies from those companies trying to bring new products to the clinic. In theory this should speed up the approval process. Critics worry that this will result in a lowering of standards and bring products to the clinic that haven’t been properly tested (According to disclosures, 58 pharmaceutical companies, 24 device companies and 26 “biotech products and research” companies have spent more than $192 million on lobbying for this new law).

2. Patient groups. As we mentioned above, patient advocacy groups have lobbied very hard for this new law (spending $4.6 million according to disclosures). The law also includes the allowance for more patient input in the drug development and approval process. This aspect alone will be a boost to the clout of such groups.

3.  Health information technology companies. The law urges federal agencies and health providers nationwide to use electronic health records systems and to collect data to enhance research and treatment (the only caveat here is that this section is unfunded by the new law). Computer companies were apparently very keen on this aspect of the new law, however, as they too have been lobbying hard.

We wanted to write that Medical schools and research hospitals may benefit since the law provides $4.8 billion over 10 years in additional funding to the federal government’s main biomedical research organisation, National Institutes of Health (NIH). It should be noted, however, that these funds are not guaranteed and will be subject to annual appropriations. So we’ll hold off stating that research is a winner until this is resolved.

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President Obama hard at work. Source: Fastcompany

Losers:

1.  Preventive medicine groups. $3.5 billion — about 30 percent — of the Prevention and Public Health Fund will be cut. This fund was established under ‘Obamacare’ to promote prevention of Alzheimer’s disease, hospital acquired infections, chronic illnesses and other ailments. Obviously certainly things have to be cut in order to fund other aspects of this new law, but this particular cut is going to hurt some affected groups.

2.  The FDA. While the FDA will be given an additional $500 million (through to 2026), this amount is not enough to cover the additional workload resulting from the law. In addition, the agency has been pushing hard for extra funding to deal with deteriorating facilities, but there was nothing to cover this in the new law.

In addition, the FDA has to deal with the renewal of a controversial voucher system which rewards companies that receive approval for new treatments dealing with ‘rare pediatric diseases‘. Upon approval the company will receive a voucher that can be redeemed later and allows the company to receive a priority review of a marketing application for a different product.

3.  Randomised clinical trials. The gold standard for testing the safety and efficacy of new drugs and devices is the randomised clinical trial. The new law, however, directs the FDA to evaluate the use of “real world evidence” for approval of new indications for FDA-approved drugs. This may result in randomised clinical trials will become less important for drug and device approval.

Currently getting a drug or a medical device approved by the FDA and into the clinic, companies have to go through a rigorous screening process, included randomized double-blind clinical trials. With the 21st Century Cures Act, that process will be sped up by allowing the use of anecdotal evidence and observational data to clear a drug for approval. That is to say, patient feedback might be used to help get drugs into the clinic more quickly.

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Source: DunnHumby

Getting treatments to the clinic sooner is a good though, right?

Critics of the new law, such as Public Citizen’s Health Research Group, are worried that the new law is relaxing the standards too much. For example they believe the designation of  “breakthrough” devices is too broad, and could lead to clearance of devices that aren’t ready for the market.

Neutral as we are here at the SoPD, we have to agree that there is the potential for real problems here. While we are as desperate as everyone else in the Parkinson’s community for new treatment, we have to be sure that those novel therapies are safe. Any lowering of standards will increase the likelihood of ineffective treatments coming to market.

What does it all mean for Parkinson’s disease?

There are a lot of positives for the Parkinson’s community resulting from this new law:

1.  The development of infrastructure to collect data on neurological diseases to better understand Parkinson’s is a good thing.

As the Micheal J Fox Foundation (MJFF) points out, we currently do not have really accurate information about how many people are living with Parkinson’s disease, let alone where they are located or who they are based on gender, ethnicity, etc. Critical pieces of information might be missing from our understanding of the disease based on the absence of such information.

2.  Extra funding for the Obama administration research initiatives to further our knowledge of the brain and developing individualized treatments is a good thing.

The ‘Cures law’ has allocated $1.5 billion over the next ten years to the NIH for the BRAIN Initiative. This will have benefits for Parkinson’s research. In addition, $30 million has been allocated for clinical research to further the field of regenerative medicine using stem cells.

3.  Speeding up the regulatory process and accounting for ‘real world observations’

The new law will make it easier for companies to bring new treatments to the clinic. Reducing the number of tests, and thus reducing the regulatory cost, may result in pharmaceutical companies being prepared to take more treatments to the FDA for approval.

In addition, the FDA will now be required to take patient perspectives into account in the drug approval process and the new law tasks the agency with creating a framework for collecting patient experience data.

This data will be collected from various sources (patients, family members and caregivers, patient advocacy organizations, disease research foundations, researchers and drug manufacturers), and it will detail a patient’s experience with a disease or therapy, taking into account the impact it has on their lives.

By involving patients/carers/families in this manner, it is hoped that government regulators will be more in touch with the community’s experiences and priorities as new drugs and devices enter late-stage clinical testing and move toward FDA approval.

What does it all mean?

It will be interesting to see how this new law impacts medical regulators globally. The US FDA is already considered to be a ‘fast mover’ when compared with other regulatory bodies. Whether these international counterpart will follow suit will be interesting to watch.

Bring treatments to market quicker, having more information regarding disease, and having a more patient-centric approach are all good aspects to this new law. As we have suggested above, however, there will be new potential for the system to be abused. Profit motivated companies will naturally look to game this new law to get their products to market.

And this may well result in medical practitioners being confronted by that double-edged sword dilemma we discussed at the start of this post. For now, all we can really so is sit back and see what happens.

If we thought 2016 was full of surprises, we can only imagine what 2017 will bring!

The banner for today’s post was sourced from Fanshare

Gene therapy in Parkinson’s disease

~ Simon ~ 6 Comments

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Exciting new last week from a small biotech company called Voyager Therapeutics which is using gene therapy to treat neurodegenerative disease. Their primary product (VY-AADC01)  is focused on Parkinson’s disease and the initial results look very positive.

The press release has indicates that the treatment is well tolerated and has beneficial effects on the subject’s motor functions. This last part is very interesting as the trial is being conducted on people with advanced Parkinson’s disease.

In today’s post, we’ll review the technology and what the results mean.

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Gene therapy. Source: HuffingtonPost

In Parkinson’s disease, we often talk about the loss of the dopamine neurons in the midbrain as a cardinal feature of the disease. When people are diagnosed with Parkinson’s disease, they have usually lost approximately 50-60% of the dopamine neurons in an area of the brain called the substantia nigra.

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The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source: Memorangapp

The midbrain is – as the label suggests – in the middle of the brain, just above the brainstem (see image below). The substantia nigra dopamine neurons reside there.

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Location of the substantia nigra in the midbrain. Source: Memorylossonline

The dopamine neurons of the substantia nigra generate dopamine and release that chemical in different areas of the brain. The primary regions of that release are areas of the brain called the putamen and the Caudate nucleus. The dopamine neurons of the substantia nigra have long projections (or axons) that extend a long way across the brain to the putamen and caudate nucleus, so that dopamine can be released there.

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The projections of the substantia nigra dopamine neurons. Source: MyBrainNotes

In Parkinson’s disease, these ‘axon’ extensions that project to the putamen and caudate nucleus gradually disappear as the dopamine neurons of the substantia nigra are lost. When one looks at brain sections of the putamen after the axons have been labelled with a dark staining technique, this reduction in axons is very apparent over time, especially when compared to a healthy control brain.

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The putamen in Parkinson’s disease (across time). Source: Brain

Previously we have discussed replacing the loss dopamine by transplanting dopamine producing cells into the putamen (click here to read that post), but some researchers now believe that this is not necessary. Instead they have proposed using gene therapy for Parkinson’s disease.

What is gene therapy?

The gene therapy involves inducing cells to produce proteins that they usually do not. This is usually done using genetically modified viruses which have had all the disease causing component removed, allowing us to use the virus as an efficient delivery system. Viruses by their very nature are very good at infecting cells, so if we remove the disease causing components, what is left is a very effective delivery system. Taking this approach one step further, we could next take genes involved with dopamine synthesis and insert them into our empty virus. By then injecting this virus into the brain, we could produce dopamine in any infected cells (it’s slightly more complicated than that, but you get the basic idea).

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Gene therapy for Parkinson’s disease. Source: Wiki.Epfl

This approach demonstrated amazing results in preclinical studies in the lab, but the transition to the clinic has not been easy (click here for a good review of the field).

What has been done in the clinic for gene therapy and Parkinson’s disease?

The first clinical attempt at gene therapy for Parkinson’s disease involved injecting a virus containing a gene called glutamic acid decarboxylase (GAD), which is an enzyme involved in the production of a chemical called GABA. The virus was injected into an area of the brain called the subthalamic nucleus, which becomes over-active in Parkinson’s disease. By ectopically producing GAD in the subthalamic nucleus, researchers were able to reduce the level of activity (this is similar to deep brain stimulation in Parkinson’s disease which modulates the activity of the subthalamic nucleus). The clinical trials for GAD produced modest results. The virus was well tolerated, but the clinical effect was limited.

Another clinical trial attempted to cause cells in the putamen to produce a chemical called neurturin (which is very similar to GDNF – we have previously written about GDNF, click here to read that post). The goal of the study was to prove neuroprotection and regeneration to the remaining dopamine neurons, by releasing neurturin in the putamen. Subjects were injected in the putamen with the virus and then the participants were followed for 15 months. Unfortunately, this study failed to demonstrate any meaningful improvement in subjects with Parkinson’s disease.

So what were the results of the trial?

Voyager Therapeutics‘s gene therapy product, VY-AADC01 is an adeno associated virus that carries a gene called Aromatic L-amino acid decarboxylase (or AADC).

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AAV Viruses. Source: HuffingtonPost

Yeah, I know: what is AADC?

AADC is the enzyme that converts L-dopa into dopamine. L-dopa can be naturally produced in the brain from Tyrosine that is absorbed from the blood. It is also the basic component of many treatments for Parkinson’s disease.

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The production of dopamine. Source: Slideplayer

By injecting VY-AADC01 into the putamen of people with advanced Parkinson’s disease, Voyager is hoping to alleviate the motor features of the condition by allowing the brain to produce a constant supply of dopamine in the exact location that is missing the dopamine (remember, the putamen is where dopamine is released). This approach will not cure the disease, but it may make life a lot easier for those affected by it.

The phase 1b clinical trial was designed to assess whether the virus had any negative side effects in humans. After the subjects were injected in the brain with VY-AADC01, they were assessed at six and twelve months after the surgery. The results suggest that the virus was well tolerated and resulted in increased AADC enzyme activity, enhanced response to L-dopa treatment, and clinically meaningful improvements in various measures of patients’ motor function (44% improvement in ‘off medication’ measures and 55% improvement in ‘on medication’ measures).

The company currently has 2 groups of subjects injected with the virus (two different concentrations) and they are looking to have a third group injected in early 2017. Phase 2 trials are planned to begin in late 2017.

What does it all mean?

Well, this is a very interesting result and bodes well for other companies taking similar gene therapy approaches (these include Oxford BioMedica and Genepod Therapeutics).

They are also interesting results because the subjects involved in the study all have advanced Parkinson’s disease (the average time since diagnosis in the subject was 10 years). So it is very positive news to see beneficial effects in later stage subjects.

Our ability to delivery of genes to different locations is a symbol of how far we have come with our understanding of biology. The fact that this knowledge is now having a positive impact in the medical world is very exciting. Gene therapy is one treatment approach that we here at SoPD are very excited about and watching very closely.

The banner for today’s post was sourced from  Voyager Therapeutics

Milk (Yes, milk) and Parkinson’s disease

~ Simon ~ 12 Comments

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We have previously written about the enormous contribution that the ‘Honolulu Heart Study’ has made to our understanding of Parkinson’s disease. This longitudinal study of 8006 “non-institutionalized men of Japanese ancestry, born 1900-1919, resident on the island of Oahu” has provided some with amazing insight to this condition by  allowing us to go back and look at what variables were apparent before people were diagnosed with Parkinson’s disease (Click here to read that post).

Earlier this year, some researchers associated with the study reported an interesting observation.

It involved milk.

In today’s post, we’ll discuss what milk might taught us about Parkinson’s disease.

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United Providers of Milk. Source: RSPB

In essence, milk is a pale liquid extracted from the mammary glands of mammals.

Riveting stuff, huh?

Ever since glandular skin secretions began with the evolutionary precursors to mammals – the synapsids – milk has remained the primary source of nutrition for infants. In addition to providing sustenance during early life, however, milk also contains colostrum which transfers elements of the mother’s own immune system (specifically antibodies) to the offspring. This exchange gives junior some extra help in strengthening their own developing immune system.

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The synapsids family – proto mammals. Source: Feenixx

As infants grow, there is the process of weaning which gradually introduces the infant to a proper diet and reduces the need for the mother’s milk.

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A proper diet. Source: Huffington Post

Now this basic idea of milk sustaining and aiding infants worked just fine until about 10,000 years ago, when we humans began doing something rather different:

We began drinking the milk from other mammals.

Sounds disgusting when you write it like that, I know, but between 7000-9000 years ago in south west Asia humans began drinking a lot more milk. Initially sheep’s milk, as it wasn’t until the 14th century that cow’s milk actually became more popular. But today there are more than 250 million cow producing milk for a dairy consuming population of over 6 billion people (despite the fact that milk can be be made in a laboratory – read more here: Cow-less milk).

Drinking milk certainly has it’s benefits:

  • one of the best sources of calcium for the body.
  • filled with Vitamin D that helps the body absorb calcium.
  • contributes to stronger and healthier bones/teeth
  • rehydration

But have you ever considered whether there is any downside to drinking milk?

Because there are.

For example, drinking too much milk can impair a child’s ability to absorb iron and given that milk has virtually no iron in it, this can result in increased risk of iron deficiency.

And then, of course, there is that thing that the Honolulu Heart Study told us about milk and Parkinson’s disease.

What did the Honolulu Heart Study tell us about milk and Parkinson’s disease?

The Honolulu Heart Study – a longitudinal study of “non-institutionalized men of Japanese ancestry, born 1900-1919, resident on the island of Oahu” –  began in October 1965. In all, 8,006 participants were studied and followed for the rest of their lives (Click here for more on this). 128 of the 8006 individuals enrolled in the study went on to develop Parkinson’s disease, and when the researchers went back and looked at the detail of their lives, they noticed something interesting about milk.

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Title: Consumption of milk and calcium in midlife and the future risk of Parkinson disease
Authors: Park M, Ross GW, Petrovitch H, White LR, Masaki KH, Nelson JS, Tanner CM, Curb JD, Blanchette PL, Abbott RD.
Journal: Neurology. 2005 Mar 22;64(6):1047-51.
PMID: 15781824

The researcher found that the incidence of Parkinson’s disease increased with milk intake. In fact, it jumped from 6.9/10,000 person-years in men who consumed no milk to 14.9/10,000 person-years in men who consumed >16 oz/day (approx. 1/2 a litre; p = 0.017). This result suggested that drinking a large cup of milk per day doubled your chances of developing Parkinson’s disease. The researchers noted that this effect was independent of calcium intake. Calcium (from both dairy and nondairy sources) inferred no increase/decrease in the risk of developing Parkinson’s disease. The effect was specific to milk.

Has anyone replicated this finding?

Unfortunately, yes. Two independent groups have found similar results:

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Title: Consumption of dairy products and risk of Parkinson’s disease.
Authors: Chen H, O’Reilly E, McCullough ML, Rodriguez C, Schwarzschild MA, Calle EE, Thun MJ, Ascherio A.
Journal: Am J Epidemiol. 2007 May 1;165(9):998-1006.
PMID: 17272289               (This article is OPEN ACCESS if you would like to read it)

These researchers looked at the subjects (57,689 men and 73,175 women) enrolled in the American Cancer Society’s Cancer Prevention Study II Nutrition Cohort, and found a total of 250 men and 138 women with Parkinson’s disease. Dairy product consumption was positively associated with risk of Parkinson’s disease, 1.8 times that of normal in men and 1.3 times in women. When the dairy products were divided into milk, cheese, yogurt and ice cream, only milk remained significantly associated with an increased risk of developing Parkinson’s disease. 

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Title: Dietary and lifestyle variables in relation to incidence of Parkinson’s disease in Greece.
Authors: Kyrozis A, Ghika A, Stathopoulos P, Vassilopoulos D, Trichopoulos D, Trichopoulou A.
Journal: Eur J Epidemiol. 2013 Jan;28(1):67-77.
PMID: 23377703

In this third study, the researchers conducted a population-based prospective cohort study involving 26,173 participants in the EPIC-Greece cohort. After analysing their data the investigators also found a strong positive association between the consumption of milk and Parkinson’s disease. And like the previous study, there was no association with cheese or yoghurt. The effect was again specific to milk.

So what is there something in particular in milk causing this effect?

That is the assumption, but we are not clear on what it is exactly. There is some new evidence, however, hinting that certain contaminants.

And this brings us to the research report from earlier this year:

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Title: Midlife milk consumption and substantia nigra neuron density at death
Authors: Abbott RD, Ross GW, Petrovitch H, Masaki KH, Launer LJ, Nelson JS, White LR, Tanner CM.
Journal: Neurology. 2016 Feb 9;86(6):512-9.
PMID: 26658906

In this study, the researchers looked at the milk intake data for 449 men in the Honolulu Heart Study (which were collected from 1965 to 1968), and then conducted postmortem examinations of their brains (between 1992 to 2004). The researchers found that subjects who drank more than 2 cups of milk per day during their midlife years had approximately 40% fewer dopamine neurons (in certain areas of a region called the substantia nigra where the dopamine neurons live).

But here is the interesting twist in the story:

None of these 449 subjects were diagnosed with Parkinson’s disease

These were all neurologically normal/healthy individuals.

Plus this particular effect was only observed among the milk drinking, non-smokers. The milk drinking smokers did not have this cell loss (smoking is associated with a reduced risk of developing Parkinson’s disease – click here for more on this).

The researchers then took the study a step further. They  noticed that the cell loss effect was also associated with the presence of heptachlor epoxide in the brain.

What is heptac..whatever?

Heptachlor is an organochlorine compound that was used as an insecticide. Pesticides and insecticides have long been associated with increased risk of Parkinson’s disease (click here to read that post).

In this study, of the 116 brains analysed, heptachlor epoxide was found in 90% of the non-smokers who drank the most milk, but only 63% of those subjects who drank no milk. This lead the researchers to speculate as to whether contamination of milk by heptachlor epoxide could have caused the cell loss. We should point out here that this particular part of the analysis is a wee bit flimsy. The sample size for the non-smoking, high milk consumption group was very small: only 12 individuals.

So what does it all mean?

It means I am now dairy free.

EDITORIAL NOTE HERE: While we do not expect this post to crash the world wide milk market, we did not want to frighten any readers out of their habit of drinking milk. It should be noted here that the daily intake of milk associated with increased risk of Parkinson’s disease is very high (>16 oz/day or 1/2 a litre/day). Having said that lowering ones dairy intake does have many benefits for ones health.

In addition, in our last post, we discussed the microbiome of the gut and how the bacteria there could be influencing Parkinson’s disease. It would be interesting to see whether follow-up studies of that particular study highlight any insecticide/pesticide interactions with the bacteria of the gut.

One last thing: The purpose of today’s post was not to scare people out of drinking milk, but merely to throw a curious observation out there for people to think about. It will be interesting to hear what people think about this, especially any observations based on their own experience.

 

The banner for today’s post was sourced from AndFarAway

Gut reaction to Parkinson’s disease

~ Simon ~ 6 Comments

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In the world of scientific research, if you publish your research in one of the top peer-reviewed journals (eg. Cell, Nature, or Science) that means that it is pretty important stuff.

This week a research report was published in the journal Cell, dealing with the bacteria in our gut and Parkinson’s disease. If it is replicated and confirmed, it will most certainly be considered REALLY ‘important stuff’.

In today’s post we review what the researchers found in their study.

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Bacteria in the gut. Source: Huffington Post

Although we may think of ourselves as individuals, we are not.

We are host to billions of microorganisms. Ours bodies are made up of microbiomes – that is,  collections of microbes or microorganisms inhabiting particular environments and creating “mini-ecosystems”. Most of these bacteria have very important functions which help to keep us healthy and functioning normally. Without them we would be in big trouble.

One of the most important microbiomes in our body is that of the gut (Click here for a nice short review on this topic). And recently there has been a lot of evidence that the microbiome of our gut may be playing a critical role in Parkinson’s disease.

What does the gut have to do with Parkinson’s disease?

We have previously written about the connections between the gut and Parkinson’s disease (see our very first post, and subsequent posts here, here and here), and there are now many theories that this debilitating condition may actually start in the gastrointestinal system. This week a new study was published which adds to the accumulating evidence.

So what does the new study say?

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Title: Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease
Authors: Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK
Journal: Cell, 167 (6), 1469–1480
PMID: 27912057                           (this article is available here)

The researchers (who have previously conducted a great deal of research on the microbiome of the gut and it’s interactions with the host) used mice that have been genetically engineered to produce abnormal amounts of alpha synuclein – the protein associated with Parkinson’s disease (Click here for more on this). They tested these mice and normal wild-type mice on some behavioural tasks and found that the alpha-synuclein producing mice performed worse.

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A lab mouse. Source: USNews

The researchers then raised a new batch of alpha-synuclein producing mice in a ‘germ free environment’ and tested them on the same behavioural tasks. ‘Germ free environment’ means that the mice have no microorganisms living within them.

And guess what happened:

The germ-free alpha-synuclein producing mice performed as well as on the behavioural task as the normal mice. There was no difference in the performance of the two sets of mice.

How could this be?

This is what the researchers were wondering, so they decided to have a look at the brains of the mice, where they found less aggregation (clustering or clumping together) of alpha synuclein in the brains of germ-free alpha-synuclein producing mice than their ‘germ-full’ alpha-synuclein producing mice.

This result suggested that the microbiome of the gut may be somehow involved with controlling the aggregation of alpha-synuclein in the brain. The researchers also noticed that the microglia – helper cells in the brain – of the germ-free alpha-synuclein producing mice looked different to their counterparts in the germ-full alpha-synuclein producing mice, indicating that in the absence of aggregating alpha synuclein the microglia were not becoming activated (a key feature in the Parkinsonian brain).

The researchers next began administering antibiotics to see if they could replicate the effects that they were seeing in the germ-free mice. Remarkably, alpha-synuclein producing mice injected with antibiotics exhibited very little dysfunction in the motor behaviour tasks, and they closely resembling mice born under germ-free conditions.

 

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How antibiotics work. Source: MLB

Antibiotics kill bacteria via many different mechanisms (eg. disrupting the cell membrane or targeting protein synthesis; see image above), and they have previously demonstrated efficacy in models of Parkinson’s disease. We shall come back to this in a section below.

The researchers in the study next asked if the microbiome of people with Parkinson’s disease could affect the behaviour of their germ free mice. They took samples of gut bacteria from 6 people who were newly diagnosed (and treatment naive) with Parkinson’s disease and from 6 healthy age matched control samples. These samples were then injected into the guts of germ free mice… and guess what happened.

The germ-free mice injected with gut samples from Parkinsonian subjects performed worse on the behavioural tasks than those injected with samples from healthy subjects. This finding suggested that the gut microbiome of people with Parkinson’s disease has the potential to influence vulnerable mice.

Note the wording of that last sentence.

Importantly, the researchers noted that when they attempted this experiment in normal mice they observed no difference in the behaviour of the mice regardless of which gut samples were injected (Parkinsonian or healthy). This suggests that an abundance of alpha synuclein is required for the effect, and that the microbiome of the gut is exacerbating the effect.

So what does it all mean?

If it can be replicated (and there will now be a frenzy of research groups attempting this), it would be a BIG step forward for the field of Parkinson’s disease research. Firstly, it could represent a new and more disease-relevant model of Parkinson’s disease with which drugs can be tested (it should be noted however that very little investigation of the brain was made in this study. For example, we have no idea of what the dopamine system looks like in the affected mice – we hope that this analysis is ongoing and will form the results of a future publication).

The results may also explain the some of the environmental factors that are believed to contribute to Parkinson’s disease. Epidemiological evidence has linked certain pesticide exposure to the incidence Parkinson’s disease, and the condition is associated with agricultural backgrounds (for more on this click here). It is important to reinforce here that the researchers behind this study are very careful in not suggesting that Parkinson’s disease is starting in the gut, merely that the microbiome may be playing a role in the etiology of this condition.

The study may also mean that we should investigate novel treatments focused on the gut rather than the brain. This approach could involve anything from fecal transplants to antibiotics.

EDITORIAL NOTE HERE: While there are one or two anecdotal reports of fecal transplants having beneficial effect in Parkinson’s disease, they are few and far between. There have never been any comprehensive, peer-reviewed preclinical or clinical studies conducted. Such an approach, therefore, should be considered EXTREMELY experimental and not undertaken without seeking independent medical advice. We have mentioned it here only for the purpose of inserting this warning.

Has there been any research into antibiotics in Parkinson’s disease?

You might be surprised to hear this, but ‘Yes there has’. Numerous studies have been conducted. In particular, this one:

antibiotic

Title: Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease.
Author: Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM.
Journal: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14669-74.
PMID: 11724929                   (This article is OPEN ACCESS if you would like to read it)

In this research study, the researchers gave the antibiotic ‘Minocycline’ to mice in which Parkinson’s disease was being modelled via the injection of a neurotoxin that specifically kills dopamine neurons (called MPTP).

Minocycline is a tetracycline antibiotic that works by inhibiting bacterial protein synthesis. It has also been shown to exert neuroprotective effects in different models of neurodegeneration via several pathways, primarily anti-inflammatory and inhibiting microglial activation.

The researchers found that Minocycline demonstrated neuroprotective properties in cell cultures so they then tested it in mice. When the researchers gave Minocycline to their ‘Parkinsonian’ mice, they found that it inhibited inflammatory activity of glial cells and thus protected the dopamine cells from dying (compared to control mice that did not receive Minocycline).

Have there been any clinical trials of antibiotic?

Again (surprisingly): Yes.

title1

Title: A pilot clinical trial of creatine and minocycline in early Parkinson disease: 18-month results.
Authors: NINDS NET-PD Investigators..
Journal: Clin Neuropharmacol. 2008 May-Jun;31(3):141-50.
PMID: 18520981                (This article is OPEN ACCESS if you would like to read it)

This research report was the follow up of a 12 month clinical study that can be found by clicking here. The researchers had taken two hundred subjects with Parkinson’s disease and randomly sorted them into the three groups: creatine (an over-the-counter nutritional supplement), minocycline, and placebo (control). All of the participants were diagnosed less than 5 years before the start of the study.

At 12 months, both creatine and minocycline were noted as not interfering with the beneficial effects of symptomatic therapy (such as L-dopa), but a worrying trend began with subjects dropping out of the minocycline arm of the study.

At the 18 month time point, approximately 61% creatine-treated subjects had begun to take additional treatments (such as L-dopa) for their symptoms, compared with 62% of the minocycline-treated subjects and 60% placebo-treated subjects. This result suggested that there was no beneficial effect from using either creatine or minocycline in the treatment of Parkinson’s disease, as neither exhibited any greater effect than the placebo.

Was that the only clinical trial?

No.

Another clinical trial, targeted a particular type of gut bacteria: Helicobacter pylori (which we have discussed in a previous post – click here for more on that).

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Title: Eradication of Helicobacter pylori infection improves levodopa action, clinical symptoms and quality of life in patients with Parkinson’s disease.
Authors: Hashim H, Azmin S, Razlan H, Yahya NW, Tan HJ, Manaf MR, Ibrahim NM.
Journal: PLoS One. 2014 Nov 20;9(11):e112330.
PMID: 25411976                (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers recruited 82 people with Parkinson’s disease. A total of 27 (32.9%) of those subjects had positive tests for Helicobacter pylori, and those participants had significantly poorer clinical scores compared to Helicobacter pylori-negative subjects. The researcher gave the participants a drug that kills Helicobacter pylori, and then twelve weeks later the researchers found improvements in levodopa onset time and effect duration, as well as better scores in motor performance and quality of life measures.

The researchers concluded that the screening and eradication of Helicobacter pylori is inexpensive and should be recommended for people with Parkinson’s disease, especially those with minimal responses to levodopa. Other experiments suggest that Helicobacter pylori is influencing some people’s response to L-dopa (click here for more on that).

Some concluding thoughts

While we congratulate the authors of the microbiome study published in the journal Cell for an impressive piece of work, we are cautious in approaching the conclusions of the study.

All really good research will open the door to lots of new questions, and the Cell paper published last week has certainly done this. But as we have suggested above, the results need to be independently replicated before we can get to excited about them. So while the media may be making a big fuss about this study, we’ll wait for (and report here) the follow-up, replication studies by independent labs before calling this REALLY ‘important stuff’.

Stay tuned.

The banner for today’s post was sourced from the Huffington Post

A new LAG in Parkinson’s

~ Simon ~ 3 Comments

blame-lag-10-copy

We have talked a lot about a protein called Alpha Synuclein on this blog (see our primer page here and our previous post).

It is very closely associated with Parkinson’s disease, given that people with genetic mutations in the alpha synuclein gene are more vulnerable to the condition, AND the protein is a key component in the disease-related circular aggregations (called ‘Lewy bodies’) in the brain. Recently researchers have identified proteins that may be involved with the transfer of Alpha Synuclein between cells – the method by which the disease is believed to be spreading. By blocking or removing these proteins, the researchers have been able to block the transfer of alpha synuclein.

In this post, we will review the research and discuss what this could mean for Parkinson’s disease.

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Science conference. Source: JPL

At the recent annual Society for Neuroscience conference in sunny San Diego, Dr Ravindran Kumaran, a neuroscientist in the laboratory of Professor Mark Cookson (at the National Institute on Aging in Bethesda, Maryland) stood up and presented data about an interesting protein that few people in the audience had ever heard of.

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Title: High-content siRNA screen identifies cellular modifiers of pre-formed alpha-synuclein fibril uptake
Authors: Kumarani R, Fernandez D, Werner-Allen JW, Buehler E, Bax A, Lai-Nag M, Cookson MR.
Source: Click here to see the full abstract

Dr Kumaran and his colleagues had systematically removed the function of each gene – one by one – in cell cultures of human cancer cells, and then measured the efficiency of the cells to absorb (or ‘take up’) the Parkinson’s related protein, alpha synuclein. An absolutely laborious task (remember there are over 20,000+ genes), but when they turned off a gene called TM9SF2, something amazing happened:

The cells absorbed 75% less of the free floating alpha synuclein than normal health cells.

This caused a bit of excitement in the Parkinson’s research community. Here was a potential method of blocking the spreading of alpha synuclein.

The funny thing is: few people had ever heard of TM9SF2, and yet Dr Kumaran then showed that TM9SF2 is in the top 3% of all proteins present in the brain. In fact, the highest concentrations of TM9SF2 are in the substantia nigra and other brain regions that are most affected by Parkinson’s disease.

So you can hopefully understand why some people in the Parkinson’s research community thought that this was a wee bit exciting.

Plus, this data presentation came on the back of another study that was published in September which presented another protein (called Lag3) that exhibited a similar ability to reduce the absorption of alpha synuclein:

lag3

Title: Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3.
Authors: Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, Kang HC, Zhang J, Xu J, Chen R, Park H, Andrabi SA, Kang SU, Gonçalves RA, Liang Y, Zhang S, Qi C, Lam S, Keiler JA, Tyson J, Kim D, Panicker N, Yun SP, Workman CJ, Vignali DA, Dawson VL, Ko HS, Dawson TM.
Journal: Science. 2016 Sep 30;353(6307).
PMID: 27708076

In this study, the researchers conducted a screen of 352 proteins that sit on the membrane of cells. They were measuring the level of alpha synuclein binding. They identified three interesting candidates for further investigation, include lymphocyte-activation gene 3 (LAG3), neurexin 1β, and amyloid β precursor-like protein 1 (APLP1).

When the researchers compared the three, they found that by removing LAG3 less alpha synuclein was taken into the cell (by endocytosis) than the other two proteins. In addition, when they increased the amount of LAG3 that a cell produces, they observed a similar increase in the amount of alpha synuclein absorbed by cells.

Next the researchers investigated the transmission of alpha synuclein between brain cells in both normal cells and cells that had no LAG3, and they found not only that LAG3 is required for the transmission, but the absence of LAG3 reduces the damage caused by the transmission.

Finally the researchers used small proteins (antibodies) to bind to and block LAG3, and they observed less transmission and damage caused by alpha synuclein. In their conclusions, the authors pointed out that LAG3 is not the only protein involved with the transmission of alpha synclein – there will be others – but it represents a potential future target for therapeutic intervention in Parkinson’s disease.

So what does this mean?

If the theory of alpha synuclein – that this protein is passed between cells, causing the spread of the disease – is correct, then any agent that can block that transmission should slow down or halt Parkinson’s disease. We have previously talked about vacines and antibodies against alpha synuclein being tested in the clinic (Click here, here and here for more on this), but blocking TM9SF2 and LAG3 represent a new method of preventing the transmission of alpha synuclein. This is very exciting. The more angles of attack that we have for designing a treatment the better our options.

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Schematic of how LAG3 may be working. Source: Science

We will be watching the field very closely and will keep you posted as new information comes to hand.

The banner for today’s post is sourced from Keepcalm-o-matic

Get more EGCG. Drink green tea.

~ Simon ~ 12 Comments

green-tea-leaves

We have previously written about the benefits of drinking coffee in reducing one’s chances of developing Parkinson’s disease (Click here for that post). Today, however, we shift our attention to another popular beverage: Tea.

Green tea in particular. Why? Because of a secret ingredient called  Epigallocatechin Gallate (or EGCG).

Today’s post will discuss why EGCG may be of great importance to Parkinson’s disease.

cup and teapot of linden tea and flowers isolated on white

Anyone fancy a cuppa? Source: Expertrain

INTERESTING FACT: after water, tea is the most widely consumed drink in the world.

In the United Kingdom only, over 165 million cups of tea were drunk per day in 2014 – that’s a staggering 62 billion cups per year. Globally 70 per cent of the world’s population (over the age of 10) drank a cup of tea yesterday.

Tea is derived from cured leaves of the Camellia sinensis, an evergreen shrub native to Asia.

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The leaves of  Camellia sinensis. Source: Wikipedia

There are two major varieties of Camellia sinensis: sinensis (which is used for Chinese teas) and assamica (used in Indian Assam teas). All versions of tea (White tea, yellow tea, green tea, etc) can be made from either variety, the difference is in the processing of the leaves.

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The processing of different teas. Source: Wikipedia

There are at least six different types of tea based on the way the leaves are processed:

  • White: wilted and unoxidized;
  • Yellow: unwilted and unoxidized but allowed to yellow;
  • Green: unwilted and unoxidized;
  • Oolong: wilted, bruised, and partially oxidized;
  • Black: wilted, sometimes crushed, and fully oxidized; (called “red tea” in Chinese culture);
  • Post-fermented: green tea that has been allowed to ferment/compost (“black tea” in Chinese culture).

(Source: Wikipedia)

More than 75% of all tea produced in this world is considered black tea, 20% is green tea, and the rest is made up of white, Oolong and yellow tea.

What is the difference between Green tea and Black tea?

Green tea is made from Camellia sinensis leaves that are largely unwilted and heated through steaming (Japanese style) or pan-firing (Chinese style), which halts oxidation so the leaves retain their color and fresh flavor. Black tea leaves, on the other hand, are harvested, wilted and allowed to oxidize before being dried. The oxidation process causes the leaves to turn progressively darker.

So what does green tea have to do with Parkinson’s disease?

In 2006,this research paper was published:

egcg-1-title

Title: Small molecule inhibitors of alpha-synuclein filament assembly
Authors: Masuda M, Suzuki N, Taniguchi S, Oikawa T, Nonaka T, Iwatsubo T, Hisanaga S, Goedert M, Hasegawa M.
Journal: Biochemistry. 2006 May 16;45(19):6085-94.
PMID:16681381

In this study, the researchers tested 79 different chemical compounds for their ability to inhibit the assembly of alpha-synuclein into fibrils. They found several compounds of interest, but one of them in particular stood out: Epigallocatechin Gallate or EGCG

imgf000007_0001

The chemical structure of EGCG. Source: GooglePatents

Now, before we delve into what exactly EGCG is, let’s take a step back and look at what is meant by the “assembly of alpha-synuclein into fibrils” (???).

Alpha Synuclein

We have previously written a lot about alpha synuclein (click here for our primer page). It is a protein that has been closely associated with Parkinson’s disease for some time now. People with mutations in the alpha synuclein gene are more vulnerable to developing Parkinson’s disease, and the alpha synuclein protein is found in the dense circular clumps called Lewy bodies that are found in the brains of people with Parkinson’s disease.

Fig2_v1c

A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia

What role alpha synuclein plays in Parkinson’s disease and how it ends up in Lewy bodies is the subject of much research and debate. Many researchers, however, believe that it all depends on how alpha synuclein ‘folds’.

The misfolding of alpha synuclein

When a protein is produced (by stringing together amino acids in a specific order set out by RNA), it will then be folded into a functional shape that do a particular job.

Alpha synuclein is slightly different in this respect. It is normally referred as a ‘natively unfolded protein’, in that is does not have a defined structure. Alone, it will look like this:

PBB_Protein_SNCA_image

Alpha synuclein. Source: Wikipedia

By itself, alpha synuclein is considered a monomer, or a single molecule that will bind to other molecules to form an oligomer (a collection of a certain number of monomers in a specific structure). In Parkinson’s disease, alpha-synuclein also aggregates to form what are called ‘fibrils’.

as-oligos

Microscopic images of Monomers, oligomers and fibrils. Source: Brain

Oligomer versions of alpha-synuclein are emerging as having a key role in Parkinson’s disease. They lead to the generation of fibrils and may cause damage by themselves.

oligomers

Source: Nature

It is believed that the oligomer versions of alpha-synuclein is being passed between cells – and this is how the disease may be progressing – and forming Lewy bodies in each cells as the condition spreads.

For this reason, researchers have been looking for agents that can block the production of alpha synuclein fibrils and stabilize monomers of alpha synuclein.

And now we can return to EGCG.

What is EGCG?

Epigallocatechin Gallate is a powerful antioxidant. It has been associated with positive effects in the treatment of cancers (Click here for more on that).

And as the study mentioned near the top of this blog suggested, EGCG is also remarkably good at blocking the production of alpha synuclein fibrils and stabilizing monomers of alpha synuclein. If the alpha synuclein theory of Parkinson’s disease is correct, then EGCG could be the perfect treatment.

f6-large

EGCG blocks the formation of oligomers. Source: Essays in Biochemistry

And there have been many studies replicating this effect:

n

Title: EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity
Authors: Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, Neugebauer K, Wanker EE.
Journal: Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7710-5. doi: 10.1073/pnas.0910723107.
PMID: 20385841            (This article is OPEN ACCESS if you would like to read it)

In this particular study, the researchers found that EGCG has the ability to not only block the formation of of alpha synuclein fibrils and stabilize monomers of alpha synuclein, but it can also bind to alpha synuclein fibrils and restructure them into the safe form of aggregated monomers.

And again, what has Green tea got to do with Parkinson’s disease?

Green tea is FULL of EGCG.

In the production of Green tea, the picked leaves are not fermented, and as a result they do not go through the process of oxidation that black tea undergoes. This leaves green tea extremely rich in the EGCG, and black tea almost completely void of EGCG. Green tea is also superior to black tea in the quality and quantity of other antioxidants.

What clinical studies have been done on EGCG and Parkinson’s disease?

Two large studies have looked at whether tea drinking can lower the risk of Parkinson’s disease. Both studies found that black tea is associated with a reduced risk of Parkinson’s disease, but one of the studies found that drinking green tea had no effect (Click here and here for more on this). Now the positive effect of black tea is believed to be associated with the high level of caffeine, which is a confounding variable in these studies. Even Green tea has some caffeine in it – approximately half the levels of caffeine compared to black tea.

The levels of EGCG in these studies were not determined and we are yet to see a proper clinical trial of EGCG in Parkinson’s disease. EGCG has been clinically tested in humans (Click here for more on that), so it seems to be safe. And there is an uncompleted clinical trial of EGCG in Huntington’s disease (Click here for more) which we will be curious to see the results of.

So what does it all mean?

Number 1.

It means that if the alpha-synuclein theory of Parkinson’s disease is correct, then more research should be done on EGCG. Specifically a double-blind clinical trial looking at the efficacy of this antioxidant in slowing down the condition.

Number 2.

It means that I now drink a lot of green tea.

Usually mint flavoured (either Teapigs or Twinnings – please note: SoPD is not a paid sponsor of these products, though some free samples would be appreciated!).

It’s very nice. Have a try.

The banner for today’s post was sourced from WeightLossExperts

Update – ISCO Stem cell Transplantation trial

~ Simon ~ 5 Comments

 

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Science conference. Source: JPL

This week over 40,000 neuroscientists from all over the world have gathered for the annual Society for Neuroscience conference in sunny San Diego. It is 5 days of non-stop presentations of scientific results.

One of the presentations made this year was delivered by Dr Russell Kern, executive vice president and chief scientific officer of International Stem Cell Corp (ISCO). It dealt with the controversial on-going stem cell clinical trial in Australia. In the presentation, Dr Kern outlined the study and gave an update on the first patient in the Phase 1 clinical trial, who was transplanted at the end of July. The second patient is scheduled be treated in the next three weeks. A total of 12 are expected to be treated.

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During the three months following the first surgery, the attending physicians observed no signs of complications (which is a very good thing). Unfortunately, according to San Diego Union Tribute, Dr Kern is then said to have implied that ‘there are some indications of efficacy in relieving symptoms of the movement disorder’. In addition, Dr Kern suggested that ‘the patient’s handwriting has improved’.

Long time readers of this blog know that we have been extremely critical of this trial from the start (Click here and here to read them). We make no apologise for this. The pre-clinical data that has been presented thus far in no way justifies taking these particular cells to the clinic. We believe it irresponsible. And our opposition is supported by many other researchers in the Parkinson’s research field (Click here for an example).

It defies belief, however, that Dr Kern would suggest to a conference audience or a media outlet that a patient who is 3 months post surgery could be exhibiting functional improvements. It is widely acknowledged in the Parkinson’s disease research field that it takes 2-3 years for the cells (that are transplanted into the brain) to mature and become functional (click here for more on this). In addition, during their preclinical studies Dr Kern and his colleagues observed very little in the way of behavioural improvements 12 months after transplantation (when compared to control conditions), so how is it that they are seeing such rapid improvements in their first human subject?

If Dr Kern’s suggestions of functional improvements are based solely on the unblinded observations of the clinician and the patient, then sharing such information publicly is extremely inappropriate. Unprofessional at best, but potentially unethical. At the very least, any suggestions of functional recovery in cases like these should be supported by brain scans (indicating increases in dopamine activity) and blinded, unbiased investigator scoring. Otherwise any reported outcomes could simply be due to the placebo effect (as the patient knows that he has been transplanted), and thus not valid for a Parkinson’s community desperate to see positive results in a potential therapy.

We also have concerns regarding the financial feasibility of the current study. Shares in ISCO have fallen from their giddy highs of $2.50 a share back in 2010 to a recent all-time low of just $0.055 (valuing the company at less than $6 million). According to their most recent financial statement, the company is burning $343,000 per month (for the year ended December 31, 2015), and the company ended 2015 with a cash position of just over $530,000. They partly resolved this problem in March of this year by issuing more shares (Source), but one does worry that this kind of activity can not be maintained indefinitely.

Here at the SoPD, we are very keen for cell transplantation to become a viable treatment option for people with Parkinson’s disease in the very near future. But the approach must be rigorously tried and tested, and presented to the highest standards before it can be considered feasible. As we have said before, the standards surrounding this particular trial (demonstrated by inappropriate disclosures of information during an ongoing clinical trial) are lacking.

FULL DISCLOSURE – The author of this blog is associated with research groups conducting the current Transeuro transplantation trials and the proposed G-Force embryonic stem cell trials planned for 2018. He has endeavoured to present an unbiased coverage of the news surrounding this current clinical trial, but when unacceptable statements are being made to media outlets, well, he is human and it is difficult to remain unbiased. He shares the concerns of the Parkinson’s scientific community that the research supporting the current Australian trial is lacking in its thoroughness, and will potentially jeopardise future work in this area. 

It is important for all readers of this post to appreciate that cell transplantation for Parkinson’s disease is still experimental. Anyone declaring otherwise (or selling a procedure based on this approach) should not be trusted. While we appreciate the desperate desire of the Parkinson’s community to treat the disease ‘by any means possible’, bad or poor outcomes at the clinical trial stage for this technology could have serious consequences for the individuals receiving the procedure and negative ramifications for all future research in the stem cell transplantation area. 

Something different – Government funding for Parkinson’s research

~ Simon ~ Leave a comment

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Here at SoPD we try to remain politically neutral.

That said, we do have a vested interest when it comes to political events and their impact on government research funding for Parkinson’s disease (or simply medical research in general).

In the wake of the recent BREXIT vote in the UK and the poll-defining victory of Mr Donald Trump in the US presidential elections, there have been many in the research community who are expressing concerns about the future of research funding.

In this post we thought it would be interesting to have a look at US and UK Government research funding and where things may be heading after the election of Mr Trump and the BREXIT vote.

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US Federal R&D spending over time. Source: Business insider

What is the current situation for federal research funding in the USA?

According to the American Association for the Advancement of Science (AAAS), the US federal government appropriates almost $140 billion per year to research and development. That is a remarkably big number (it is more than the entire GDP of Hungary!).

The grandeur of this number, however, hides a disturbing fact. That $140 billion is down from a 2010 peak of about $160 billion (in constant dollars – inflation adjusted). And this reduction in funding has had trickle down effects.

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The NIH headquarters in Maryland, USA. Source: NPR

The National Institute for Health (NIH) is one of the largest funders of medical research in the world. In 2015 it had a budget of $31,381 million. More than 83 percent of their budget goes to more than 300,000 research personnel at over 3,000 universities, medical schools, and other research institutions in the USA and around the world (Source: NIH). Few other research funding institutions wield the kind of power that the NIH has.

Again, however, the impressive numbers hides a secret.

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NIH funding from 2003 – 2015. Source: FASEB

As displayed in the graph above, from 2003 to 2015, NIH funding from the US government dropped by 22% of its capacity to fund research due to budget cuts, sequestration, and inflationary losses.

In very real terms, medical research funding from the US federal Government has been falling – and this started long before the global financial crisis.

What is the current situation for Government research funding in the UK?

uk-funding-1

 

Research funding in the UK. Source: Keith’s Blog

The UK spends approximately £25bn per year on research.While not as impressive as our cousins across the pond, that number is still a large chunk of change. Approximately 1/3 (£7.98bn) comes from the UK Government. And again that sounds like a lot of money, but here is the terrible truth of the matter:

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Science research funding as a % of GDP. Source: Scienceogram

At a time where the population is ageing and requiring more assistance due to conditions like Parkinson’s disease, we are spending less (based on GDP) on research than most of our neighbours. Yes, we are still recovering for the global economic crisis (9 years and counting, dear bankers), but the trend for the UK in the graph above is of some concern. Especially when you consider that back in the 1980s the UK was spending over 2% of GDP on research:

uk-funding2

The difference in % of GDP spent on research between 1985 and 2007. Source: Keith’s Blog

For academic research, there are seven Research Councils that receive funding from the Government’s Science Budget. Each year, they invest around £3 billion in research, covering the full spectrum of academic disciplines. This arrangement may change shortly, with all of the seven councils coming together under one umbrella: Research UK (but that is an entirely different controversy – click here for more on this).

A total investment of £26.3 billion has been planned by the Government between 2016/17 to 2020/21 (Source: Gov.uk), but this may well change in the wake of BREXIT. All eyes in the UK are focused on the Autumn budget statement on Wednesday 23 November. This will be the first confirmation from Theresa May’s government as to their stance on research funding.

In addition to Government funding of research, the UK research community has benefitted considerably from belonging to the EU. Between 2007 to 2013, the UK contributed nearly £4.3bn towards EU research projects, BUT it received nearly £7bn back over the same period. That £2.7bn excess was equivalent to more than £400m in research funds a year. By leaving the EU, this enormous stream of funding is now in jeopardy.

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The UK is the leading country in terms of number of projects won from Horizon 2020. Source: LSE

We remain fully paid-up members of Horizon 2020, the EU’s eighth Framework Programme for funding research and innovation, and as the graph above shows we are one of the most successful countries in the EU with regards to projects being awarded funding. The Horizon 2020 scheme has a total budget of just over €70 billion for funding research until 2020. But beyond that…

Critically for researchers, the lack of clarity in the UK position with the EU leaves the potential for international collaborations up in the air.

So what is the outlook for the US?

The good news is that historically new Republicans presidents generally spend more on research than democrats:

spending

New president spending on research. Source: ChicagoPolicyReview

The bad news is that much of that increase is predominantly on the defence research side of things (Click here to read more on this – the original study).

Mr Trump has given little indication regarding his thoughts on research funding. And it is difficult to get any real sense of where things may be going based on the mass media news outlets, which seem to be more interested in scandal rather than in depth investigative journalism.

Mr Trump has been quoted as saying:

“Though there are increasing demands to curtail spending and to balance the federal budget, we must make the commitment to invest in science, engineering, healthcare, and other areas that will make the lives of Americans better, safer and more prosperous. We must have programs such as a viable space program and institutional research that serve as incubators to innovation and the advancement of science and engineering in a number of fields.”

Adding, however:

“In a time of limited resources, one must ensure that the nation is getting the greatest bang for the buck. We cannot simply throw money at these institutions and assume that the nation will be well served.”

Source: Science Debate

Mr Trump appears to be intent on bringing the US federal deficit under control. But he has also indicated plans for cutting taxes (for all incomes), eliminating the estate tax, and providing a significant child care credit. He believes that the increased economic activity resulting from these cuts would counteract that drop in tax income. Such policies do not bode well for research funding (an easy section of the budget to reduce).

With regards to neurodegeneration research, during the election campaign Mr Trump told a New Hampshire audience that Alzheimer’s was a “total top priority” for him. So there may be some hope there for closely associated Parkinson’s disease (we can hope).

We will simply have to wait and see.

And what is the outlook for the UK?

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The winning team in the BREXIT vote. Source: Telegraph

The UK’s public finances have worsened by approximately £25 billion since the March Budget (source: Independent), with the impact of the BREXIT vote apparently being a major contributing factor. This hole in the finances is going to require the Government to borrow more and spend less, which may well impact research funding in the up coming Autumn budget statement. And the Autumn statement is causing very real concerns for many in the research community (Click here for a recent editorial in the journal Nature).

To counter any reduction in the levels of Government research funding, incentives could be put in place for commercial/industrial resources to step in. The pharmaceuticals industry accounts for 48% of all corporate research funding in the UK, and much of this funding is at the University research institute level.

With regards to the huge pot of EU funding that could be lost, the UK could ‘buy-back’ into the EU research programmes as an ‘Associated Member’. But this approach would have several major drawbacks:

  • No political say into the formation and direction of future research funding programmes.
  • A 12% contribution of funds requirement for just a 16% gain of competitive funds.
  • Any changes to UK immigration policies at any stage would cause major disruption to future programmes.

Obviously clarity is required. We will wait to see what the Autumn statement brings.

EDITORIAL NOTE: I have tried to remain unbiased here, ignoring much of the negative comments in the media regarding Mr Trump’s proposed policies and the BREXIT related scaremongering in the UK. It is however difficult to sort through the mess and differentiate fact from opinion. This post was never intended to be a post, just a personal investigation of the state of play in research funding for Parkinson’s disease. But I decided to share it here for general interest (and I hope it was of interest). It is a very serious matter.

The banner for today’s post was sourced from Lucas Jackson/Reuters

Prothena reports Phase 1b results for Parkinson’s immunotherapy

~ Simon ~ 12 Comments

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This week the biotech company Prothena released the results of their phase 1b clinical trial for their treatment, PRX002 (also known as RG7935).

This is one of the first immuno-therapies being tested in Parkinson’s disease, and the results indicate that the treatment was active and well tolerated.

In this post we will review the press release and what it tells us regarding this clinical trial.

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Antibodies binding to proteins. Source: AXS

When your body is infected by a foreign agent, it begins to produce some things called antibodies. In most cases, these are Y-shaped proteins that binds to the un-wanted invader and act as a beacon for the immune system. It is a very effective system, allowing us to go about our daily business without getting sick on a regular basis. Antibodies allow us to build up immunity, or resistance of an organism to infection or disease.

Scientist have harnessed the power of this natural process, and they have use it to develop methods of helping our bodies fight off disease.

The first approach is called Acquired Immunity (or adaptive immunity), and it is based on the idea that exposure of the immune system to a pathogen (disease/damage causing agent) creates an ‘immunological memory’ within our immune system, and this leads to an enhanced response to subsequent future encounters with that same pathogen.

Scientists have used the idea of acquired immunity to develop what we call vaccines – which are simply small, neutral fragments of specific pathogen that help the immune system to build up immunity (or resistance) before the body is attacked by the disease-causing pathogen itself.

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Vaccination. Source: WebMD

The second approach is called Passive Immunity.

Passive immunisation is simply the sharing of antibodies. And that might sound a bit disturbing, but it is actually a naturally occurring process. For example, a mother’s antibodies are transferred to her baby in the womb via the placenta.

And again, scientists have devised ways of producing passive immunisation artificially. And recently researchers have been using this approach to attack many medical conditions (particularly cancer), in an area of medicine called immunotherapy.

Think of it as simply boosting the immune system by supplementing the supply of antibodies. Scientists can produce high levels of antibodies that specifically target a particular pathogen and then transfer those antibodies to affected people via an intravenous injection.

How is this being used for Parkinson’s disease?

Well, we have previously discussed the idea of a vaccine for Parkinson’s disease (click here to read that post), and we have been closely following the progress of an Austrian company, AffiRis, who are leading the vaccination approach (Click here for that post).

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Source: AffiRis

The vaccine approach is targeting the Parkinson’s disease associated protein, Alpha synuclein. It is believed that a bad kind of alpha synuclein is causing the spread of the condition, by being passed from cell to cell. The goal of the vaccine is to capture and remove all of the alpha synuclein being passed between cells and thus (hopefully) halt the progress of – or at least slow down – the disease.

And this week, another company – Prothena – has reported the results of their phase 1 trial for a passive immunity approach to Parkinson’s disease. They have been injecting subjects in the trial with a treatment called PRX002.

(Remember that a phase 1 trial simply tests the safety of a treatment in humans, it is not required to test efficacy of the treatment. Efficacy comes with phases 2 & 3 trials)

What is PRX002?

PRX002 is a monoclonal antibody. The scientists at the biotech company Prothena have artificially produced large amounts of antibodies to alpha synuclein and these have been injected into people with Parkinson’s disease.

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Monoclonal antibodies. Source: Astrazeneca

Prothena provide a short video explaining this concept (click here to view the video).

So what were the results of the Prothena study?

The study was conducted in collaboration the pharmaceutical company Roche. It was a double-blind (so both the researchers and subjects did not know what they were receiving until the conclusion of the study), placebo-controlled study involving 80 people with Parkinson’s disease. The subjects were randomly assigned to one of six groups, which received either PRX002 or a placebo. There were six doses of PRX002 tested in the study (0.3, 1, 3, 10, 30 or 60 mg/kg).

The study was conducted over six-month, during which patients received three once-a-month injections of either PRX002 or placebo. The subjects were then followed for an observational period of three months.

According to the press release, no serious treatment-related adverse events were reported in PRX002 treated patients. Mild treatment-related adverse events (greater than anything experienced within the placebo group) were noted in 4 of the 12 subjects in the highest dosage group of PRX002, including constipation and diarrhoea.

Importantly, the investigators reported that thePRX002 antibodies were crossing the blood brain barrier and entering the brain. This resulted in a rapid reduction of alpha-synuclein levels (in some cases by up to 97 percent after a single dose!).

The follow-on Phase 2 clinical study is expected to begin in 2017.

What is the difference between the vaccine and the passive immunity approaches?

Basically, it comes down to levels of control. With a vaccination, once you have injected the vaccine and the immune system is activated, there isn’t much you can do to control the response of the body. And that immune memory is going to last a long time. The passive immunity response, on the other hand, requires regular injections of antibodies which can be stopped if adverse effects are noted.

Plus – and forgive me if I sound a little bit cynical here – drug companies prefer a regular treatment approach (which they can charge for each visit) compared to a one-shot cure. It’s simply a better business model.

What happens next?

In both cases – the vaccine and the passive immunity approaches – phase 2 trials are being set up by the respective companies and we will wait to see have affective these treatments are at slowing down Parkinson’s disease.

If they are affective, expect big headlines in the media and plans for adults everywhere to start being vaccinated. If they fail,…. well, we will have to re-address our understanding of the role of alpha synuclein in Parkinson’s disease.

Interesting times lie ahead.

The banner for todays post was sourced from Prothena

The benefits (???) of Antioxidants

~ Simon ~ 5 Comments

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It seems everyday we read stories in the media about the benefits of these things called antioxidants. We are repeatedly told that we ‘need more antioxidants in our diet’, because they will help to stave off debilitating conditions like Parkinson’s disease.

Last week, however, a study was published which indicates that this may not be the case.

In todays post we look at antioxidants and their impact on Parkinson’s disease.

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Berries are a wonderful source of antioxidants. Source: Steroidal

Antioxidants are one of those subjects that is often discussed, but not well understood. So before we review the study that was published last week, let’s first have a look at what we mean when we talk about antioxidants.

What is an antioxidant?

An antioxidant is simply a molecule that prevents the oxidation of other molecules.

OK, but what does that mean?

Well, the cells in your body are made of molecules. Molecules are combinations atoms of one or more elements joined by chemical bonds. Atoms consist of a nucleus, neutrons, protons and electrons.

Oxidation is the loss of electrons from a molecule, which in turn destabilises the molecule. Think of iron rusting. Rust is the oxidation of iron – in the presence of oxygen and water, iron molecules will lose electrons over time. Given enough time, this results in the complete break down of objects made of iron.

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Rust, the oxidation of metal. Source: TravelwithKevinandRuth

The exact same thing happens in biology. Molecules in your body go through a similar process of oxidation – losing electrons and becoming unstable. This chemical reaction leads to the production of what we call free radicals, which can then go on to damage cells.

What is a free radical?

A free radical is an unstable molecule – unstable because they are missing electrons. They react quickly with other molecules, trying to capture the needed electron to re-gain stability. Free radicals will literally attack the nearest stable molecule, stealing an electron. This leads to the “attacked” molecule becoming a free radical itself, and thus a chain reaction is started. Inside a living cell this can cause terrible damage, ultimately killing the cell.

Antioxidants are thus the good guys in this situation. They are molecules that neutralize free radicals by donating one of their own electrons. The antioxidant don’t become free radicals by donating an electron because by their very nature they are stable with or without that extra electron.

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How free radicals and antioxidants work. Source: h2miraclewater

What are good sources of antioxidants?

While human being are pretty poor at producing antioxidants, plants produce LOTS! Thus vegetables and fruits are a fantastic source of antioxidants.

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Sources of antioxidants (no. 3 is our favourite). Source: DrAxe

The Oxygen radical absorbance capacity (ORAC) score mentioned in the figure above is a method of measuring the antioxidant capacity of various substances. For comparative sake, a piece of tofu has an ORAC score of approximately 90, a beef steak has an ORAC score of approximately 10, and a ‘Redbull’ energy drink has an ORAC score of 0 (as they all have very few antioxidants – Source:Superfoodly).

A source of major antioxidants are vitamins (such as beta-carotene, vitamin C, and vitamin E). Vitamins are essential nutrients that our bodies needs (in small amounts) to function properly. Many of them are also potent antioxidants.

Vitamin C (or ascorbic acid), in particular, is a powerful antioxidant and it is found in both animals and plants. Unfortunately for humans, however, one of the enzymes needed to make ascorbic acid was lost by a genetic mutation during primate evolution, and so we must obtain it from our diet (eat lots of oranges folks).

How could antioxidants work for Parkinson’s disease?

 

Postmortem analysis of the brains of people who had Parkinson’s disease has revealed numerous signs of oxidative damage, and this has lead to many researchers hypothesising that oxidation is a key component of the disease.

So what research was published last week?

The results of this study:

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Title: Intake of antioxidant vitamins and risk of parkinson’s disease.
Authors: Hughes KC, Gao X, Kim IY, Rimm EB, Wang M, Weisskopf MG, Schwarzschild MA, Ascherio A.
Journal: Movement Disorders. 2016 Oct 27. doi: 10.1002/mds.26819.
PMID: 27787934

In this study, the investigators wanted to look at the consumption of antioxidant vitamins and the risk of developing Parkinson’s disease. In order to do this, they needed large pools of medical data that they could analyse. They used the databases from the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) in the USA.

NHS study was started in 1976 when 121,700 female registered nurses (aged 30 to 55 years) completed a mailed questionnaire. They provided an overview of their medical histories and health-related behaviours. The HPFS study was established in 1986, when 51,529 male health professionals (40 to 75 years) responded to a similar questionnaire. Both the NHS and the HPFS send out follow-up questionnaires every 2 years.

The investigators in the current study, removed the data from people who reported ‘implausible total energy intake at baseline (<660 or >3,500 kcal/day for women and <800 or >4,200 kcal/day for men)’, missed reporting for any survey, or had a diagnosis of Parkinson’s disease at the start of the study. This left them with the survey results of 80,750 women and 48,672 men to analyse.

From these pools of subjects, they found a total of 1036 people with Parkinson’s disease (554 in HPFS and 482 in NHS). When the investigators looked at antioxidant vitamin consumption, they found that vitamin E was not associated with an increased or decreased risk of Parkinson’s disease. Vitamin C intake showed indications of reducing the risk of developing Parkinson’s, but this not significant.

The investigators concluded that their results do not support the hypothesis that consumption of antioxidant vitamins reduces the risk of Parkinson’s disease.

What about other Parkinson’s disease research on antioxidants?

There have been several clinical trials for antioxidants and Parkinson’s disease. Of particular interest has been the research surrounding Coenzyme Q10 (also known as ubiquinone and ubidecarenone).Coenzyme Q10 is an antioxidant that exhibited positive preclinical results for Parkinson’s disease, and this led to several large clinical trials:

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Title: A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.
Authors: Parkinson Study Group QE3 Investigators., Beal MF, et al.
Journal: JAMA Neurol. 2014 May;71(5):543-52.
PMID: 24664227

This article reported the results of a phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites, consisting of 600 participants. While Coenzyme Q10 was safe and well tolerated by the subjects in the study, it demonstrated no evidence of clinical benefit.

One justified critique of this study, however, was the variety of subjects with Parkinson’s disease involved in the study. It has been suggested that a clinical trial should be performed with coenzyme Q10 in people with Parkinson’s disease who have a proven mutation in the PINK1 gene as these are the subjects who are most likely to benefit from this approach. That would be an interesting trial.

So what does it all mean?

Well, the study published last week needs to be replicated with another large database before any serious conclusions can be made. For all the hype around antioxidants, however, there is a worrying lack of supporting evidence that they actually have any effect (in the case of lung cancer there are even suggestions that some vitamin antioxidants could exacerbate the situation – click here for more on this).

The results of the study reviewed above do suggest that our view of oxidation in Parkinson’s disease needs to be re-addressed. It may be that oxidation may simply be an end step in the condition, and trying to block it with antioxidants is fruitless.

It should be noted that we are not suggesting here that people should stop taking antioxidants – they are an important part of any balanced diet, necessary for normal biological functioning. We are simply presenting the evidence that some of the hype surrounding their potential is unfounded.

As usual, as more information comes to hand, we shall present it here. Watch this space.

The banner for todays post was sourced from Pinkhope