Tagged: Science

When disco-needs-ya, can gene therapy help ya?

 

With the recent announcement that the STEADY-PD III/Isradipine clinical trial did not reach its primary end point (that of slowing the progression of Parkinson’s), the winds of change have shifted with calls for a focus on biomarkers and better treatments, rather than disease modification.

Recently, researchers at Michigan State University have reported a novel experimental gene thearpy method for dealing with one of the most debilitating aspects of Parkinson’s – dyskinesias.

Ironically, their approach involves the same calcium channels that Isradipine blocks.

In today’s post, we will look at what dyskinesias are, what gene therapy is, and how this new approach could be useful for people currently burdened by these involutary movements.

 


Dyskinesia. Source: JAMA Neurology

There is a normal course of events following a diagnosis of Parkinson’s.

Yes, I am grossly over-generalising.

And no, I’m not talking from personal experience (this is based on listening to a lot of people), but just go with me on this for the sake of discussion.

First comes the shock of the actual diagnosis. For many it is devastating news – an event that changes the course of their lives. For others, however, the words ‘you have Parkinson’s‘ can provide a strange sense of relief that their current situation has a name and gives them something to focus on.

This initial phase is usually followed by the roller coaster of various emotions (including disbelief, sadness, anger, denial). It depends on each individual.

The emotional rollercoaster. Source: Asklatisha

And then comes the period during which many will try to familiarise themselves with their new situation. They will read books, search online for information, join Facebook groups (Click here for a good one), etc.

That search for information often leads to awareness of some of the realities of the condition.

And one potential reality that causes concern for many people (especially for people with young/early onset Parkinson’s) is dyskinesias.

What are dyskinesias?

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The 2019 World Parkinson’s Congress

I have a request to make of readers.

I have been invited – with Parkinson’s advocate AC Woolnough – to conduct a round table at the upcoming 2019 World Parkinson’s Congress meeting in Kyoto. The round table is a discussion involving 10-20 people sitting around a table. Our topic will be how can we better align the efforts of researchers and patients.

And this is where we would like your help. Or at least, we would like your input.

Specifically, we are seeking topics for discussion at the table regarding how we can better join the goals/focus of the community on the research side of things.

In today’s post, we look at what the World Parkinson’s congress is, how the round table topic came about, and what we are currently thinking regarding the structure of our roundtable session.


Yasaka Pagoda and Sannen Zaka Street. Source: JT

It was the capital of Japan for more than one thousand years (from 794 to 1869).

It sits 315 miles southwest of Tokyo and 25 miles east of Osaka.

It was the setting of the world’s first novel in the world (Shikibu Murasaki’s The Tale of Genji).

It has over 1000 Buddhist temples (including the hugely impressive Fushimi-Inari-Taisha), and more than 2,000 temples and shrines collectively.

Fushimi-Inari-Taisha. Source: Medium

It has the oldest restaurant in Kyoto, Japan (called Honke Owariya, which was founded in 1465).

It had its own civil war – referred to as “Onin no Ran” (Onin War) – in the 15th century. The war lasted 11 years (1467-1477) and focused on two families of samurai warriors seeking power in Kyoto.

It is the home of the video game company Nintendo and Nightingale Floors:

It holds 20% of Japan’s National Treasures and 17 UNESCO World Heritage sites (including Kiyomizu-dera, Ryōan-ji, Saihō-ji, Tō-ji, and Kinkaku-ji.

It has 1.5 million residents (and 50 million tourists per year).

It consumes more bread and spends more money on coffee than any other city in Japan (I wonder why?).

It has the longest train platform in Japan (at JR Kyoto Station – 564 meters long!).

It is Kyoto.

Kinkaku-ji. Source: AWOL

And in June of this year, the World Parkinson’s congress will be held in this beautiful city.

What is the World Parkinson’s congress?

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Monitoring Parkinson’s: Under pressure

 

An important aspect of developing new potentially ‘curative’ treatments for Parkinson’s is our ability to accurately test and evaluate them. Our current methods of assessing Parkinson’s are basic at best (UPDRS and brain imaging), and if we do not improve our ability to measure Parkinson’s, many of those novel treatments will fail the clinical trial process and forever remain just “potentially” curative.

Blood pressure issues are a common feature of Parkinson’s that does not get a lot of attention, but new technology could provide us with new insight.

In today’s post, we look at new technology (under development) which could be applied to Parkinson’s, for the measuring and assessment of blood pressure, and we will look at how it could be used in certain clinical trials.

 


Apple watch 4 (not an endorsement). Source: NewScientist 

Late last year, the tech giant Apple released yet more new versions of their phones and watches (with much fanfare). And before we continue: this is not an advertisement or endorsement (unless Apple wants to talk to me???… ).

Of interest was the new version of their watch, which has a handy feature of being able to tell you when you have fallen over (a warning that one was about to fall would surely be more useful, no?).

Useful feature, but those buttons are rather close for anyone with a tremor. Source: ATT

And much was made about the ability of the watch to monitor heart rate, which is a very clever trick, particularly for people with atrial fibrillation (periods of abnormal activity in the atrials of the heart) – although there appear to a few issues to be ironed out (Click here to read more about this).

Source: USAtoday

Many of these smart watches and wrist band monitoring gadgets can now detect heart rate, but monitoring of blood pressure would actually be more useful for the Parkinson’s community.

What does blood pressure have to do with Parkinson’s?

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I’ve got gum disease on my mind

 

Earlier this year, a San Francisco-based biotech company – called Cortexyme – published a research report that grabbed my attention.

The study presented data supporting an alternative theory of the cause of Alzheimer’s – one in which a bacteria involved in gum disease appears to be playing a leading role – and evidence that the company’s lead experimental compound COR388 could have beneficial effects in the treatment of the condition.

While the study was intriguing, what completely blew my mind was the fact that the company had already tested COR388 in a couple of Phase I clinical trials, and since then they have initiated a large Phase II/III trial.

In today’s post, we will discuss this new theory of Alzheimer’s, look at what Cortexyme are doing, and how this could relate to Parkinson’s.

 


The dashed lines show associations. Source: Slideplayer

Before we start today’s post, a word on ‘associations‘.

Please remember while reading this material that association does not equate to causation.

So if I write something like “researchers have found an association between a type of bacteria that causes gum disease and Alzheimer’s”, it does not mean that someone with either condition necessarily has the other. It only means that they have both simply appeared in the same individuals at a higher than chance rate.

All clear?

Yes.

Good.

So what is today’s post about?

A very interesting report in which researchers have found an association between a type of bacteria that causes gum disease and Alzheimer’s.

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Monthly Research Review – April 2019

 

At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during April 2019.

The post is divided into seven parts based on the type of research:

  • Basic biology
  • Disease mechanism
  • Clinical research
  • New clinical trials
  • Clinical trial news
  • Other news
  • Review articles/videos

 


So, what happened during April 2019?

In world news:

10th April – Scientists from the Event Horizon Telescope project announced the first ever image of a black hole. Located in the core of the Messier 87 galaxy (53 million light years from Earth), this supermassive black hole has a mass 6.5-billion times that of the Sun! The black hole’s boundary – the event horizon – is around 2.5 times smaller than the shadow it casts and measures just under 40 billion km across (about the size of Neptune’s orbit!!!).

 

10th April – Fossil fragments found in the Callao Cave in the Philippines revealled the existence of a new species of human, Homo luzonensis. The species is named after the island – Luzon – where it was discovered.

 

15th April – During Holy Week, a devastating fire engulfed the roof and main spire of Notre-Dame Cathedral in Paris.

 

24th April – I am a big fan of Martin. Several years ago his video of the Marble machine took the internet by storm and since then I have been following his regular vlog updates on the construction of the new and improved Marble machine X. This week he took the  new machine for its first test run – still has parts missing, but this is mesmerising to watch. If you don’t follow him you should!

 

In the world of Parkinson’s research, a great deal of new research and news was reported:

In April 2019, there were 730 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (3134 for all of 2019 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 9 pieces of Parkinson’s news

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All we need to do is block CD22?

 

Microglia are the resident immune cells in the brain – they maintain law and order when trouble kicks off.  And when things get really bad, these cells change shape, become “activated”, and start to absorb toxins, debris and anything else that they feel should not be there – via a process called phagocytosis.

And they are ruthless in this task.

When we are young, these cells function very well at maintaining a general sense of ‘homeostasis‘ (or stable equilibrium). But as we age,… well, let’s just say things start to slip a little.

Recently a group of researchers at Stanford University have discovered by inhibiting a single protein, called CD22, they can restore microglial homeostasis in the ageing brain, and this had beneficial effects in a model of Parkinson’s.

In today’s post, we will look at what microglia are, what phagocytosis is, and what these new CD22 results could mean for Parkinson’s.

 


Source: Brucesallan

My father often says: Ageing is not for sissies.

And as the birthdays have started to mount up, I’ve come to better understand what he means.

There are days when I feel like an old man trapped in a 27 year old’s body. For the record, I’m 27. And for the record, I’m going to be 27 until I die (27 was a great year!).

An amazing journey. Source: Topsimages

While some are able (and foolishly gleeful) to avoid taxes, until recently no one has been able to escape the rentless march of ageing. Until recently, the vast majority of us have been resigned to our fates. And until recently, the fountain of youth has only existed in the realm of the Hollywood movies.

The force is strong with this one. Source: Reddit

Until recently?

Recently there has been an enormous amount of research focused on stopping ageing and preventing death (both of which are being viewed as “curable diseases” – click here to read more about this). Now to be honest, much of this is still quackery.

But there does seem to be progress being made in the biology of extending ‘healthspan’ (as opposed to lifespan).

And some of that research could have implications for Parkinson’s.

Such as?

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A fine time for Felodipine?

 

Researchers at the University of Cambridge have published an interesting research report last week regarding a clinically available drug that they suggest boosts autophagy in the brain.

Autophagy is one of several processes that cells use to dispose of waste and old proteins.

The drug is called Felodipine, and it is a calcium channel blocker that is used to treat high blood pressure.

In today’s post, we will look at what autophagy is, how boosting it could help with neurodegenerative conditions, and whether Felodipine should be clinically tested for re-purposing to Parkinson’s.

 


Source: Novusbio

This is Prof David Rubinsztein (blue shirt) and the members of his research lab at the Cambridge Institute for Medical Research (CIMR) in Cambridge (UK).

Prof Rubinsztein is the Deputy Director of the CIMR, the Academic Lead of the UK Alzheimer’s Research UK Cambridge Drug Discovery Institute, and he is a group leader at the UK Dementia Research Institute at the University of Cambridge.

He is also one of the world’s leading experts in the field of autophagy in neurodegenerative conditions.

What is autophagy?

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The other GDNF clinical trial

 

Glial cell-line derived neurotrophic factor (or GDNF) has been a topic of heated discussion in the Parkinson’s community for a long time. Most recently due to the announcement of the results of the Phase II Bristol GDNF clinical trial results, which did not meet the primary end points of the study (Click here to read more about that).

This week at the annual American Association of Neurological Surgeons conference in San Diego, the results of another GDNF clinical trial were presented.

This new study was a Phase I study assessing the safety and tolerability of a gene therapy approach for GDNF in people with Parkinson’s.

In today’s post, we will discuss what gene therapy is, what the new trial results indicate, and what the researchers may be planning to do next for this new clinical trial programme.

 


Source: AANS

Every year members of the American Association of Neurological Surgeons gather together in one spot and compare data/research/clinical notes.

This year the 87th AANS Annual Scientific Meeting was held in spectacular San Diego.

San Diego. Source: AFP

From Saturday 13th April through till Wednesday 17th, clinicians and researchers attended lectures and discussed new data on every aspect of neurological surgery. While I did not (nor planned to) attend the meeting, I was very interested to learn more about one particular presentation.

It involved the announcement of the results of a clinical trial which was focused on a gene therapy approach for Parkinson’s.

The treatment involved GDNF (Click here to read the abstract).

What is GDNF?

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Sonic Hedgehog (I kid you not)

 

One of the characteristic features of Parkinson’s is the loss of dopamine neurons in the brain. One experimental approach that is being explored for treating the condition involves investigating biological pathways involved in the early development of dopamine neurons.

By re-exposing the dopamine neurons to supportive, growth-encouraging proteins that are present during early development (but absent or reduced in adulthood), researchers hope to be able to rejeuvinate these cells and make them healthier.

In a recent post, we discussed one such developmental supportive protein: Glial cell derived neurotrophic factor (Click here to read more about this).

In today’s post, we will look at a different type of developmental protein which is having interesting effects in models of Parkinson’s. That protein is called Sonic Hedgehog.

 


The humble fly (Drosophila). Source: Ecolab

No one should ever be allowed to say that fly genetists don’t have a sense of humour.

When it comes to the naming of genes, they have had a great deal of fun. A gene is a section of DNA that can be copied into RNA (which may then provide the instructions for making a protein), and each gene has been given a name. Some names are boring – such as leucine-rich repeat kinase 2 (or LRRK2… Boring!) – while other names are rather amusing.

For example, there is one fly gene called indy, which stands for I‘m Not Dead Yet. Flies with genetic variation in this gene have longer than average lifespans (Click here to read more about this).

Source: Sciencemag

Another amusingly named gene is Cheap Date. Flies with a genetic mutation in this gene are very susceptible to alcohol (Click here to read more about this).

Source: Lordsofthedrinks

There is also Ken and Barbie – genetic variations in this gene result in a lack of external genitalia (Click here to read more about this). There are lots of great gene names: lunatic fringe”, “headcase” and “mothers against decapentaplegia (MAD)”. Like I said, fly genetists have a lot of fun.

But one of the most popular gene names in all of biology is a gene called Sonic Hedgehog.

What is Sonic Hedghog?

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Time to resTOR in New Zealand

 

As the amazing Australian Parkinson’s Mission project prepares to kick off, across the creek in my home land of New Zealand, another very interesting clinical trial programme for Parkinson’s is also getting started. The study is being conductetd by a US biotech firm called resTORbio Inc.

The drug being tested in the study is called RTB101.

It is an orally-administered TORC1 inhibitor, and it represents a new class of drug in the battle against Parkinson’s. 

In today’s post, we will look at what TORC1 is, how the drug works, the preclinical research supporting the trial, and what this new clinical trial will involve.

 


Rapa Nui. Source: Chile.Travel

Today’s post kicks off on an amazing south Pacific island… which is not New Zealand.

In 1965, a rather remarkable story began in one of the most remote inhabited places on Earth – the mysterious island of Rapa Nui (or “Easter Island”).

And when we say ‘remote’, we really do mean remote. Did you know, the nearest inhabited island to Rapa Nui is Pitcairn Island, which is 2,075 kilometres (1,289 mi) away. And Santiago (the capital of Chile) is 2,500 miles away – that’s a four-hour+ flight!!!

Rapa Nui is the very definition of remote. It is as remote as remote gets!

Does Amazon deliver to the town of Hanga Roa? Source: Atlasandboots

Anyways, in 1965 a group of researchers arrived at Rapa Nui with the goal of studying the local inhabitants. They wanted to investigate their heredity, environment, and the common diseases that affected them, before the Chilean government built a new airport which would open the island up to the outside world.

It was during this investigation, that one of the researchers – a University of Montreal microbiologist named Georges Nógrády – noticed something rather odd.

What?

At the time of the study, wild horses on Rapa Nui outnumbered humans (and stone statues).

Wild horses roaming the east coast of Rapa Nui. Source: Farflungtravels

But what was odd about that?

Georges discovered that locals had a very low frequency of tetanus – a bacterial infection of the feet often found in places with horses. He found this low incidence of tetanus particularly strange given that the locals spent most of their time wandering around the island barefoot. So Georges decided to divide the island into 67 regions and he took a soil sample from each for analysis.

In all of the vials collected, Nógrády found tetanus spores in just one vial.

Something in the soil on Rapa Nui was extremely anti-fungal.

In 1969, Georges’ collection of soil samples was given to researchers from the pharmaceutical company Wyeth and they went looking for the source of the anti-fungal activity. After several years of hard work, the scientists found a soil bacteria called Streptomyces hygroscopicus which secreted a compound that was named Rapamycin – after the name of the island – and they published this report in 1975:

Title: Rapamycin (AY-22, 989), a new antibiotic
Authors: Vézina C, Kudelski A, Sehgal SN.
Journal: J Antibiot (Tokyo). 1975 Oct;28(10):721-6.
PMID: 1102508              (This report is OPEN ACCESS if you would like to read it)

It is no understatement to say that this was a major moment in biomedical history. So much so that there is actually a plaque on the island commemorating the discovery of rapamycin:

Source: DiscoveryMag

Why was the discovery of ‘anti-fungal’ rapamycin so important?!?

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