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.
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:
Why was the discovery of ‘anti-fungal’ rapamycin so important?!?
Being a patriotic ‘kiwi’, I am always very pleased to write about interesting Parkinson’s research originating from the homeland. And recently the results of an interesting clinical study that was designed and conducted in New Zealand have been published.
The clinical study was focused on whether a diet manipulation could influence motor and non-motor symptoms/features of Parkinson’s.
Specifically, the researchers were looking at the low-fat versus ketogenic diets.
In today’s post, we will discuss what is meant by a ketogenic diet, we will assess the results of the study, and consider what they might mean for the Parkinson’s community.
The All Blacks. Source: Newshub
Aotearoa (also known as New Zealand) is a remarkable little country (and yes, I know I’m slightly biased).
It flies under the radar for most folks who are not interested in rugby, amazing scenery, great quality of life, or hobbits, but historically this tiny South Pacific nation of 4.6 million people has punched well above its weight on many important matters.
For example, on the 19th September 1893, the governor, Lord Glasgow, signed a new Electoral Act into law. And as a result of that simple act, New Zealand became the first self-governing country in the world in which all women (over the age of 21) had the right to vote in parliamentary election (Australia followed in 1902, the US in 1920, & the Britain in 1928). That achievement, it should be said, was the result of years of dogged effort by suffrage campaigners, led by Kate Sheppard who is today acknowledged with her portrait on the $10 note:
The NZ $10 note. Source: Whaleoil
A New Zealander made the first trans-global radio transmission on the 18th October 1924. Invalided during WWI, Frank Bell revived his childhood interest in wireless communication, and after being the first kiwi to have two-way radio contact with Australia and North America, he achieved something far more impressive. From the family sheep station in ‘Shag Valley’ (East Otago – bottom of the South Island), he sent a Morse code transmission (“Greetings from New Zealand, signed Bell Z4AA”) which was received and replied to by amateur operator Cecil Goyder at Mill Hill School (London).
Frank and his older sister Brenda. Source: NZhistory
New Zealand was also where jet boats was first invented by Sir Bill (William Hamilton). His first jet boat was a 3.6 meter (12 foot) plywood hull with a 100 E Ford engine, and the jet a centrifugal type pump. This craft was tested on the Irishman Creek dam, before it ran successfully upriver in 1953. And from there it kind of went viral. In 1960, three Hamilton jet boats (the Kiwi, Wee Red and Dock), became the first and only boats to travel all the way up through the Grand Canyon.
Sir Hamilton and his first jet boat (1958). Source: ipenz
And the list doesn’t stop there. We could go on with other great firsts:
- Sir Ed (Hillary) – first to summit Everest (to be fair, it was a team effort)
- Sir Ernest (Rutherford) – first to split the atom
- Sir Peter (Blake) – first to sail around the world in less than 75 days (again, a bit of a team effort)
- Sir John (Walker) – first to run the mile in under 3:50 (now a member of the Parkinson’s community)
- Georgina Beyer – first openly transsexual mayor, and then the world’s first openly transsexual Member of Parliament
- AJ Hackett & Henry van Asch – set up the first commercial bungy jump on the Kawarau Bridge, near Queenstown
- Helen Clark, Dame Siliva Cartwright & Sian Elias – first country to have women in the top three senior public roles (Prime Minister, the Governor General, & the Chief Justice, respectively)
- Rocket Lab – first private company in the Southern Hemisphere to reach space (in 2009)
And I guess we better stop there (if only out for fear of making larger nations feel somewhat inadequate), but you get the idea – small nation, doing lots of great stuff.
There is also a very proactive Parkinson’s community – with groups like Parkinson’s New Zealand organising and running support groups across the country, and helping to fund some of the great local Parkinson’s research.
Being a proud kiwi, I am happy to highlight and support any research coming out of New Zealand.
Recently a new commentary has been published suggesting that living in the NZ city of Rotorua (‘Roto-Vegas‘ to the locals) may decrease the risk of developing Parkinson’s disease.
In today’s post, we will review the research behind the idea and discuss what it could mean for people with neurodegenerative conditions, like Parkinson’s disease.
The geothermal wonderlands of Rotorua. Source: Audleytravel
Rotorua is a small city in the central eastern area of the North Island of New Zealand (Aotearoa in the indigenous Māori language).
The name Rotorua comes from the Māori language (‘roto’ meaning lake and rua meaning ‘two’). The full Māori name for the spot is actually Te Rotorua-nui-a-Kahumatamomoe. The early Māori chief and explorer Ihenga named it after his uncle Kahumatamomoe. But given that it was the second major lake found in Aotearoa (after lake Taupo in the centre of the North Island), the name that stuck was Rotorua or ‘Second lake’.
Maori culture. Source: TamakiMaoriVillage
Similar to lake Taupo, Rotorua is a caldera resulting from an ancient volcanic eruption (approximately 240,000 years ago). The lake that now fills it is about 22 km (14 mi) in diameter.
Lake Rotorua. Source: Teara
The volcano may have disappeared, but the surrounding region is still full of geothermal activity (bubbling mud pools and geysers), providing the region with abundant renewable power and making the city a very popular tourist destination.
Tourist playing with mud. Source: Rotoruanz
Before visiting the city, however, travellers should be warned that Rotorua’s other nicknames include “Sulphur City” and “Rotten-rua”, because of the smell that results from the geothermal activity.
And speaking from personal experience, the “rotten eggs” smell is prevalent.
Interesting, but what has this got to do with the science of Parkinson’s disease?
Well, the rotten egg smell is the result of hydrogen sulfide emissions, and recently it has been suggested that this pungent gas may be having positive benefits on people, particularly with regards to Parkinson’s disease.
This idea has been proposed by Dr Yusuf Cakmak at the University of Otago in a recent commentary:
Title: Rotorua, hydrogen sulphide and Parkinson’s disease-A possible beneficial link?
Author: Cakmak Y.
Journal: N Z Med J. 2017 May 12;130(1455):123-125.
In his write up, Dr Cakmak points towards two studies that have been conducted on people from Rotorua. The first focused on examining whether there was any association between asthma and chronic obstructive pulmonary disease and exposure to hydrogen sulfide in Rotorua. By examining air samples and 1,204 participants, the investigators of that study no association (the report of that study is OPEN ACCESS and can be found by clicking here).
The second study is the more interesting of the pair:
Title: Chronic ambient hydrogen sulfide exposure and cognitive function.
Authors: Reed BR, Crane J, Garrett N, Woods DL, Bates MN.
Journal: Neurotoxicol Teratol. 2014 Mar-Apr;42:68-76.
PMID: 24548790 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators recruited 1,637 adults (aged 18-65 years) from Rotorua. They conducted neuropsychological tests on the subjects, measuring visual and verbal episodic memory, attention, fine motor skills, psychomotor speed and mood. The average amount of time the participants had lived in the Rotorua region was 18 years (ranging from 3-64 years). The researchers also made measurements of hydrogen sulfide levels at the participants homes and work sites.
While the researchers found no association between hydrogen sulfide exposure and cognitive ability, they did notice something interesting in the measures of fine motor skills: individuals exposed to higher levels of hydrogen sulfide displayed faster motor response times on tasks like finger tapping. Finger tapping speed is an important part of Parkinson’s Motor Rating Scale examination tests.
The investigators behind the study concluded that the levels of hydrogen sulfide in Rotorua do not have any detrimental effect on the individuals living in the area,
Dr Cakmak, however, wondered whether “relatively high, but safe, hydrogen sulfide levels in Rotorua could help protect the degradation of dopaminergic neurons associated with Parkinson’s Disease?” (based on the better performance on the motor response time).
Hang on a second, what exactly is hydrogen sulfide?
Hydrogen sulfide (chemical symbol: H2S) is a colourless gas. Its production often results from the the breaking down of organic material in the absence of oxygen, such as in sewers (this process is called anaerobic digestion. It also occurs in volcanic and geothermal conditions.
H2S. Source: Wikipedia
About 15 years ago, it was found in various organs in the body and termed a gasotransmitter. A gasotransmitter is a molecule that can be used to transmit chemical signals from one cell to another, which results in certain physiological reactions (oxygen, for example, is a gasotransmitter).
Hydrogen sulfide is now known to be cardioprotective (protection of the heart), and many years of research have demonstrated beneficial aspects of using it in therapy, such as vasodilation and lowering blood pressure, increasing levels of antioxidants, inhibiting inflammation, and activation of anti-apoptotic (anti-cell death) pathways. For a good review of hydrogen sulfide’s cardioprotective properties – click here.
The demonstration of the protective properties of hydrogen sulfide in other bodily organs have led neuroscientists to start investigating whether these same benefits could be utilised in treating disorders of the brain.
And the good news is: hydrogen sulfide can have positive benefits in the brain – Click here for a good review of the brain-related research.
Has other research been conducted on hydrogen sulfide regarding Parkinson’s disease?
Yes. And here is where the story starts to get really interesting.
Then hydrogen sulfide was tested in rodent models of Parkinson’s disease:
Title: Neuroprotective effects of hydrogen sulfide on Parkinson’s disease rat models.
Authors: Hu LF, Lu M, Tiong CX, Dawe GS, Hu G, Bian JS.
Journal: Aging Cell. 2010 Apr;9(2):135-46.
PMID: 20041858 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers firstly looked at what happens to hydrogen sulfide in the brains of rodent models of Parkinson’s disease. When rats were injected with a neurotoxin (6-OHDA) that kills dopamine neurons, the investigators found a significant drop in the level of hydrogen sulfide in the region where the dopamine cells reside (called the substantia nigra – an area of the brain severely affected in Parkinson’s disease).
Next the researchers gave some rodents the neurotoxin, waited three weeks and then began administering sodium hydrosulfide – which is a hydrogen sulfide donor – every day for a further 3 weeks. They found that this treatment significantly reduced the dopamine cell loss, motor problems and inflammation in the sodium hydrosulfide treated animals. Interestingly, they saw the same neuroprotective effect when they repeated the study with a different neurotoxin (Rotenone). The investigators concluded that hydrogen sulfide “has potential therapeutic value for treatment of Parkinson’s disease”.
And this first study was followed up one year later by a study investigating inhaled hydrogen sulfide:
Title: Inhaled hydrogen sulfide prevents neurodegeneration and movement disorder in a mouse model of Parkinson’s disease.
Authors: Kida K, Yamada M, Tokuda K, Marutani E, Kakinohana M, Kaneki M, Ichinose F.
Journal: Antioxid Redox Signal. 2011 Jul 15;15(2):343-52.
PMID: 21050138 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators gave mice a neurotoxin (MPTP) and then had them breathe air with or without hydrogen sulfide (40 ppm) for 8 hours per day for one week. The mice that inhaled hydrogen sulfide displayed near normal levels of motor behaviour performance and significantly reduced levels of neurodegeneration (dopamine cell loss).
Inhalation of hydrogen sulfide also prevented the MPTP-induced activation of the brain’s helper cells (microglia and astrocytes) and increased levels of detoxification enzymes and antioxidant proteins (including heme oxygenase-1 and glutamate-cysteine ligase). Curiously, hydrogen sulfide inhalation did not significantly affect levels of reduced glutathione (we will come back to this in an upcoming post).
These first two preclinical results have been replicated many times now confirming the initial findings (Click here, here, here and here for examples). The researchers of the second ‘inhalation’ study concluded the study by suggesting that the potential therapeutic effects of hydrogen sulfide inhalation now needed to be examined in more disease relevant models of Parkinson’s disease.
And this is exactly what researchers did next:
Title: Sulfhydration mediates neuroprotective actions of parkin.
Authors: Vandiver MS, Paul BD, Xu R, Karuppagounder S, Rao F, Snowman AM, Ko HS, Lee YI, Dawson VL, Dawson TM, Sen N, Snyder SH.
Journal: Nat Commun. 2013;4:1626. doi: 10.1038/ncomms2623.
PMID: 23535647 (This article is OPEN ACCESS if you would like to read it)
The researchers conducting this study were interested in the interaction of hydrogen sulfide with the Parkinson’s disease-associated protein Parkin (also known as PARK2). They found that hydrogen sulfide actively modified parkin protein – a process called sulfhydration – and that this enhances the protein’s level of activity.
They also noted that the level of Parkin sulfhydration in the brains of patients with Parkinson’s disease is markedly reduced (a 60% reduction). These finding imply that drugs that increase levels of hydrogen sulfide in the brain may be therapeutic.
Interestingly, cells with genetic mutations in another Parkinson’s disease related gene, DJ-1, also produce less hydrogen sulfide (click here to read more about this).
Has anyone ever looked at hydrogen sulfide and alpha synuclein?
Not that we are aware of.
Alpha synuclein is the Parkinson’s disease associated protein that clusters in the Parkinsonian brain and forms Lewy bodies.
But researchers have looked at hydrogen sulfide and amyloid formation:
Title: Hydrogen sulfide inhibits amyloid formation
Authors: Rosario-Alomar MF, Quiñones-Ruiz T, Kurouski D, Sereda V, Ferreira EB, Jesús-Kim LD, Hernández-Rivera S, Zagorevski DV, López-Garriga J, Lednev IK.
Journal: J Phys Chem B. 2015 Jan 29;119(4):1265-74.
PMID: 25545790 (This article is OPEN ACCESS if you would like to read it)
Amyloid formations are large clusters of misfolded proteins that are associated with neurodegenerative conditions, like Alzheimer’s disease and Parkinson’s disease. The researchers who conducted this study were interested in the behaviour of these misfolded protein in the presence of hydrogen sulfide. What they found was rather remarkable: the addition of hydrogen sulfide completely inhibited the formation amyloid fibrils (amyloid fibril plaques are found in brains of people with Alzheimer’s disease).
If the addition of hydrogen sulfide can reduce the level of clustered proteins in a model of Alzheimer’s disease, it would be interesting to see what it would do to alpha synuclein.
NOTE: Hydrogen sulfide levels are also reduced in the brains of people with Alzheimer’s disease (click here to read more on this topic)
Has hydrogen sulfide ever been tested in the clinic?
There are currently 17 clinical trials investigating hydrogen sulfide in various conditions (not Parkinson’s disease though).
So where can I get me some of that hydrogen sulfide?
Ok, so here is where we come in with the health warning section.
You see, hydrogen sulfide is a very dangerous gas. It is really not to be played with.
The gas is both corrosive and flammable. More importantly, at high concentrations, hydrogen sulfide gas can be fatal almost immediately (>1000 parts per milllion – source: OSHA). And the gas only exhibits the “rotten eggs” smell at low concentrations. At higher concentrations it becomes undetectable due to olfactory paralysis (luckily for the folks in Rotorua, the levels of hydrogen sulfide gas there are between 20-25 parts per billion).
Thus, we do not recommend readers to rush out and load up on hydrogen sulfide gas.
There are many foods that contain hydrogen sulfide.
For example, garlic is very rich in hydrogen sulfide. Another rich source is cooked beef, which has about 0.6mg of hydrogen sulfide per pound – cooked lamb has closer to 0.9 milligrams per pound. Heated dairy products, such as skim milk, can have approximately 3 milligrams of hydrogen sulfide per gallon, and cream has slightly more than double that amount.
Any significant change in diet by a person with Parkinson’s disease should firstly be discussed with a trained medical physician as we can not be sure what impact such a change would have on individualised treatment regimes.
What does it all mean?
Summing up: It would be interesting to look at the frequency of Parkinson’s disease in geothermal region of the world (the population of Rotorua is too small for such an analysis – 80,000 people).
Researchers believe that components of the gas emissions from these geothermal areas may be neuroprotective. Of particular interest is the gas hydrogen sulfide. At high levels, it is a very dangerous gas. At lower levels, however, researchers have shown that hydrogen sulfide has many beneficial properties, including in models of neurodegenerative conditions. These findings have led many to propose testing hydrogen sulfide in clinical trials for conditions like Parkinson’s disease.
Dr Cakmak, who we mentioned near the top of this post, goes one step further. He hypothesises that hydrogen sulfide may actually be one of the active components in the neuroprotective affect of both coffee and smoking – and with good reason. It was recently demonstrated that the certain gut bacteria, such as Prevotella, are decreased in people with Parkinson’s disease (see our post on this topic by clicking here). The consumption of coffee has been shown to help improve the Prevotella population in the gut, which may in term increase the levels of Prevotella-derived hydrogen sulfide. Similarly smokers have a decreased risk of developing Parkinson’s disease and hydrogen sulfide is a component of cigarette smoke.
All of these ideas still needs to be further tested, but we are curious to see where this research could lead. An inhaled neuroprotective treatment for Parkinson’s disease may have benefits for other neurodegenerative conditions.
Oh, and if anyone is interested, we are happy to put readers in contact with real estate agents in sunny ‘Rotten-rua’, New Zealand. The locals say that you gradually get used to the smell.
EDITOR’S NOTE: Under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. While some of the drugs/molecules discussed on this website are clinically available, they may have serious side effects. We therefore urge caution and professional consultation before any attempt to alter a treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.
The banner for today’s post was sourced from Trover
I really didn’t expect to be writing about Parkinson’s research being conducted in New Zealand again so quickly, but yesterday a new study was published which has a few people excited.
It presents evidence of how the disease may be spreading… using cells collected from people with Parkinson’s disease.
In today’s post we will review the study and discuss what it means for Parkinson’s disease.
The South Island of NZ from orbit. Source: Sciencenews
We may have mentioned the protein Alpha synuclein once or twice on this blog.
For anyone familiar with the biology of Parkinson’s disease, alpha synuclein is a major player. It is either public enermy no.1 in the underlying pathology of this condition or else it is the ultimate ‘fall guy’, left standing in the crime scene holding the bloody knife.
Remind me, what is alpha synuclein?
Alpha synuclein is an extremely abundant protein in our brains – making up about 1% of all the proteins floating around in each neuron (one of the main types of cell in the brain).
In healthy brain cells, normal alpha synuclein is typically found just inside the surface of the membrane surrounding the cell body and in the tips of the branches extending from the cell (in structures called presynaptic terminals which are critical to passing messages between neurons).
And why is alpha synuclein important in Parkinson’s disease?
Genetic mutations account for 10-20% of the cases in Parkinson’s disease.
Five mutations in the alpha-synuclein gene have been identified which are associated with increased risk of Parkinson’s disease (A53T, A30P, E46K, H50Q, and G51D – these are coordinates for locations on the alpha synuclein gene). Rare duplication or triplication of the gene have also been associated with Parkinson’s disease.
The structure of alpha synuclein protein – blue squares are mutations. Source: Mdpi
So genetically, alpha synuclein is associated with Parkinson’s disease. But it is also involved at the protein level.
In brains of many people with Parkinson’s disease, there are circular clumps of alpha synuclein (and other proteins) that collect inside cells. These clumps are called Lewy bodies. They are particularly abundant in areas of the brain that have suffered cell loss.
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
No one has ever seen the process of Lewy body formation, so all we can do is speculate about how these aggregates develop. Currently there is a lot of evidence supporting the idea that alpha synuclein can be passed between cells. Once inside the new cell, the alpha synuclein helps to seed the formation of new Lewy bodies, and this is how the disease is believed to progress.
Exactly how alpha synuclein is being passed between cells is the topic of much research at the moment. There are many theories and some results implicating methods such as direct penetration, or via a particular receptor. Perhaps even by a small package called an exosome being passed between cells (see image above).
How this occurs in the Parkinson’s disease brain, however, is unknown.
And this (almost) brings us to the kiwi scientists.
Last years, a group of Swiss scientists demonstrated that alpha synuclein could be passed between cells via ‘nanotubes’ – tiny tubes connecting between cells. The outlined their observations and results in this article:
Title: Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes.
Authors: Abounit S, Bousset L, Loria F, Zhu S, de Chaumont F, Pieri L, Olivo-Marin JC, Melki R, Zurzolo C.
Journal: EMBO J. 2016 Oct 4;35(19):2120-2138.
The researchers who conducted this study were interested in tunneling nanotubes.
Yes, I know, ‘What are tunneling nanotubes?’
Tunneling nanotubes (also known as Membrane nanotubes or cytoneme are long protrusions extending from one cell membrane to another, allowing the two cells to share their contents. They can extend for long distances, sometimes over 100 μm – 0.1mm, but that’s a long way in the world of cells!
Previous studies had demonstrated that tunneling nanotubes can pass different infectious agents (HIV for example – click here to read more on this), supporting the idea that these structures could be a general conduit by certain diseases could be spreading.
A tunneling nanotube between two cells. Source: Pasteur
In their study the Swiss researchers found that alpha synuclein could be transferred between brain cells (grown in culture) via tunneling nanotubes. In addition, following that process of transfer, the alpha synuclein was able to induce the aggregation (or clumping) of the alpha synuclein in recipient cells.
A particularly interesting finding was that alpha synuclein appeared to encourage the appearance of tunneling nanotubes (there were more tunneling nanotubes apparent when cells produced more alpha synuclein). And the alpha synuclein that was being transferred was being passed on in ‘lysosomal vesicles’ – these are the rubbish bags of the cell (lysosomal vesicles are used to take proteins away for degradation).
Paints a rather insidious picture of the ‘ultimate fall guy’ huh!
And that image was made worse by the results published by the kiwis last night:
Title: α-synuclein transfer through tunneling nanotubes occurs in SH-SY5Y cells and primary brain pericytes from Parkinson’s disease patients
Authors: Dieriks BV, Park TI, Fourie C, Faull RL, Dragunow M, Curtis MA.
Journal: Scientific Reports, 7, Article number: 42984
PMID: 28230073 (This article is OPEN ACCESS if you would like to read it)
In their study, the New Zealand scientists extended the Swiss research by looking at cells collected from people with Parkinson’s disease. The researchers took human brain pericytes, which were derived from the postmortem brains of people who died with Parkinson’s disease.
And before you ask: pericytes are cells that wrap around the cells lining small blood vessels. They are important to the development of new blood vessels and maintaining the structural integrity of microvasculature.
A pericyte (blue) hugging a blood vessel (red). Source: Xvivo
Pericytes contain alpha synuclein precipitates like those seen in neurons, and the kiwi scientists demonstrated that pericytes too can transfer alpha synuclein via tunneling nanotubes to neighbouring cells – representing a non-neuronal method of transport.
They also found that the transfer through the tunneling nanotubes can be very rapid – within 30 seconds – and the transferred alpha synuclein can hang around for more than 72 hours, suggesting that it is difficult for the receiving cell to dispose of. The researchers did note that the transfer through tunneling nanotubes occurred only in small subset of cells, but that this could explain the slow progression of Parkinson’s disease over time.
What does it all mean?
In order for us to truly tackle Parkinson’s disease and bring it under control, we need to know how this slowly progressing neurodegenerative condition is spreading. Some researchers in New Zealand have provided evidence involving cells collected from people with Parkinson’s disease that indicates one method by which the disease could be passed from one cell to another.
Tiny tunnels between cells, allowing material to be shared, could explain how the disease slowly progresses. The scientists observed the Parkinson’s associated protein alpha synuclein being passed between cells and then hanging around for more than a few days.
This method of transfer was made more interesting because the New Zealand researchers reported that non-neuronal cells (Pericytes, collected from people with Parkinson’s disease) could also form tunneling nanotubes. This observation raises questions as to what role non-neuronal cells could be playing in Parkinson’s disease.
This line of questions will obviously be followed up in future research, as will efforts to determine if tunneling nanotubes are actually present in the human brain or simply biological oddities present only in the culture dish. Demonstrating nanotubes in the brain will be difficult, but it would provide us with solid evidence that this method of disease transfer could be a bonafide cause of disease spread.
We watch with interest for further work in this area.
FULL DISCLOSURE: The author of this blog is a kiwi… and proud of it. He is familiar with the researchers who have conducted this research, but has had no communication with them regarding the publishing of this post. He simply thought that the results of their study would be of interest to the Parkinson’s community.
The banner for today’s post was sourced from Pinterest
A biotech company in Australasia got the green light for the next round in a clinical trial two weeks ago.
Their product: tiny cylinders filled with pig cells.
Their mission: to treat Parkinson’s disease with the regenerative healing properties of naturally occurring cells.
In today’s post we will look at what the company is doing and what will happen next.
We have been contacted by several readers asking for a post on the press release last week regarding the clinical trial being conducted by Living Cell Technologies Limited (LCT).
Two weeks ago LCT received approval to commence the treatment of 6 patients in their third group of subjects in a Phase IIb clinical trial of NTCELL® for Parkinson’s disease, at Auckland City Hospital in New Zealand (Click here for the press release).
The company completed treatment of all six patients in ‘group 2’ of the Phase IIb clinical trial of NTCELL for Parkinson’s disease at the end of 2016. Four patients in the trial had 40 NTCELL microcapsules implanted into the putamen on each side of their brain, and two patients had sham surgery with no NTCELL implanted. They now have approval to repeat this in a third group of subjects.
What do we know about the company?
Founded in 1999, the initial goal of the company was to develop regenerative cell therapies. This goal was to be achieved by transplanting cells from Auckland Island pigs into humans.
The first disease considered for this approach was type 1 diabetes, which is now being pursued by a joint venture company in the US while LCT focuses its attention on Parkinson’s disease.
What are NTCELL microcapsules?
NTCELL is an a tiny capsule, that contains choroid plexus cells (taken from pigs). The capsule is made of a semi permeable membrane that allows all of the good chemicals and nutrients (that the cells are producing) to escape into the surrounding environment. At the same time it doesn’t let the cells escape, nor does it allow negative elements into the capsule. In addition, the bodies immune system can’t get at the foreign cells and remove them due to the membrane surrounding the capsule.
An example of encapsulated cells. Source: LEN
These capsules can be transplanted into the brain of people with neurodegenerative conditions, providing the brains of those individuals with the benefits of supportive chemicals and nutrients.
A brain scan of NTCELL capsules transplanted in the human brain. Source: LCT
Interesting, but what are choroid plexus cells?
Believe it or not, there are some empty spaces inside your brain. Spaces where there are no brain cells (neurons).
These spaces are called the ‘ventricles‘.
In the human brain there are 4 basic divisions of the ventricles as you can see in the image below (the ventricles are the yellow space):
The ventricles and choroid Plexus in the human brain (red coloured regions). Source: PhysRev
The ventricles are filled up with a solution called cerebrospinal fluid. Cerebrospinal fluid is very similar to the liquid portion of blood (or plasma – if you remove the cells from blood, it’s called plasma), except that cerebrospinal fluid is nearly devoid of protein. It is actually made from plasma, but it only contains 0.3% of plasma proteins and about 2/3 of the glucose of blood.
The choroid plexus cells are one of the primary sources of production for the cerebrospinal fluid. That production is actually great – total volume of cerebrospinal fluid in the the average human being turns over almost 4 times per day. Choroid plexus cells can be found in all 4 divisions of the ventricular system (the choroid plexus cells are indicated with red/brown colouring in the image above).
And, um… why pigs?
The choroid plexus cells are sourced from a unique herd of pigs that have been designated pathogen-free. They were originally sourced from the remote sub-Antarctic Auckland Islands, where they have been running around in isolation since 1807.
The not-so-tropical Auckland Islands, south of NZ. Source: Sciblogs
That isolation has made them ‘pathogen free’ – basically there is a reduced likelihood of endogenous infectious agents (eg. porine (pig) retrovirus (or PERVs)) in the cells – which is a good thing when you are planning to stick something in the brain.
What research has been done on NTCELL?
Firstly, regarding the capsules, the company published this report in 2009:
Title: Encapsulated living choroid plexus cells: potential long-term treatments for central nervous system disease and trauma.
Authors: Skinner SJ, Geaney MS, Lin H, Muzina M, Anal AK, Elliott RB, Tan PL.
Journal: J Neural Eng. 2009 Dec;6(6):065001.
In this study, the company looked at the utility of the capsules in rodent brains. One important aspect that they wanted to address was how well the cells survive inside the capsules when placed in the brain. They found that the capsules effectively protected the cells from the host immune system, and they survived for the length of the 6 months study without causing any adverse effects.
The capsules were retrieved from the brains of the rats at the end of the study and the viability of cells was analysed. The researchers found that there was no difference in the production of nutrients from the cells in the capsules at 4 months post implantation, but they did see a decrease of 33% at 6 months. In addition, the number of cells decreased to approximately 40% of the pre-implantation values at 6 months.
We are unsure whether the capsules have been altered for the clinical trial.
The researchers followed this research up in 2013 by publishing this paper:
Title: Recovery of neurological functions in non-human primate model of Parkinson’s disease bytransplantation of encapsulated neonatal porcine choroid plexus cells.
Authors: Luo XM, Lin H, Wang W, Geaney MS, Law L, Wynyard S, Shaikh SB, Waldvogel H, Faull RL, Elliott RB, Skinner SJ, Lee JE, Tan PL.
Journal: J Parkinsons Dis. 2013 Jan 1;3(3):275-91. doi: 10.3233/JPD-130214.
PMID: 24002224 (This article is OPEN ACCESS if you would like to read it)
The researchers wanted to test the capsules in non-human pre-clinical trials. For this purpose they induced Parkinson’s disease in 15 monkeys using the neurotoxin MPTP, waited 10 weeks and then implanted their capsules. Six monkeys were implanted with the NTCELL capsules, 6 were implanted with empty capsules, and 3 received no capsules. The animals were then tested out to 24 weeks post implantation.
The behavioural response was dramatic. Most of the primates with the NTCELL capsules demonstrated positive behavioural benefits by 2 weeks post implantation (becoming statistically significant by 4 weeks), while the controls and empty capsule groups exhibited no behavioural recovery at all across the entire 24 weeks.
In addition to behavioural benefits, the investigators found significantly more dopamine neurons in the brains of the monkeys implanted with the NTCELL capsules when compared to the controls.
These findings were used by the company to justify moving towards clinical trials in humans.
And what do we know about the clinical trial for Parkinson’s disease?
A Phase I/IIa NTCELL clinical trial for the treatment of Parkinson’s disease was completed in June 2015. It was an open label investigation of the safety and clinical effect of NTCELL in 4 people who had been diagnosed with Parkinson’s disease for at least five years.
The trial “met the primary endpoint of safety” and “reversed progression of the disease two years after implant” (as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS)). The NTCELL implantation was well tolerated, with “no adverse events considered to be related to NTCELL”. The results of the trial have not been published, but the press release can be found here.
The results from that trial were used to justify and design a larger Phase IIb trial.
What does Phase IIb mean?
Phase II studies, which are designed to address clinical efficacy and biological activity, can be divided into IIA or IIB, and while there is no stated definition for these labels it is generally agreed that:
- Phase IIA studies are usually pilot studies designed to demonstrate clinical efficacy or biological activity (‘proof of concept’ studies);
- Phase IIB studies look to find the optimum dose at which the drug shows biological activity with minimal side-effects (‘definite dose-finding’ studies) – (Source: Wikipedia).
The goal of this Phase IIb LCT clinical study is to “confirm the most effective dose of NTCELL, define any placebo component of the response and further identify the initial target Parkinson’s disease patient sub group”.
A total of 18 patients under 65 years old are taking part in the trial being conducted at Auckland Hospital and Mercy Ascot Hospital in New Zealand. The company will have to wait 26 weeks until after the last patient is implanted to know whether it has been successful in meeting regulator’s conditions on quality, safety, and efficacy. At the 26 weeks mark, the subjects that received the placebo (empty capsules) will be given the NTCELL capsules.
If the current Phase IIb trial is successful, Living Cell Technologies Limited will be looking to “apply for provisional consent to treat paying patients in New Zealand and launch NTCELL® as the first disease modifying treatment for Parkinson’s disease, in 2017” (Source: Ltcglobal). We will wait to see the results of the current study before passing judgement on whether this situation is likely, though it does seem premature given that by the end of the phase IIb trial only 20 people with Parkinson’s disease will have received the NTCELL treatment. A larger phase III trial may be required. Alternatively, if the results of the current trial are truly spectacular, the company may be able to propose a Phase IV style of trial (also called a ‘post-marketing surveillance’ trial) which would allow them to market their product, but they would be required to maintain a strict program of safety surveillance and ongoing technical analysis of the treatment.
Are other companies trying to do something similar?
Another company, NSgene (in Denmark) has a similar sort of experimental product called NsG0301 which is encapsulated human cells that express the neuroprotective protein, GDNF. NsG0301 is still in preclinical testing however, with the Michael J Fox Foundation helping the company to get the clinical trials started.
Sounds very interesting, but what does it all mean?
So in summary, the biotech company LCT have been given permission to continue with their phase II clinical trial which involves placing tiny capsules which contain cells that release beneficial nutrients into the brains of people with Parkinson’s disease. The company will be blind to which individuals are receiving the capsules with cells in them or empty capsules. They should know later in the year if the trials is successful.
One positive feature of this idea is that immune-suppressant treatments are not required as they are with other forms of transplantation therapies. This means that the patient doesn’t need to take medication which stops the immune system from attacking the foreign cells, because the cells are protected by the capsule membrane. Such medication can leave subjects with reduced immune system responses to illness and thus vulnerable.
Having said that, we are a little concerned that the NTCELL product has not been tested thoroughly enough in Parkinson’s disease for the company to be proposing it for commercial use later this year. For example, the phase I open label results could easily be the result of the placebo effect in practise (as all 4 participants knew they were receiving the capsules. This issue could be resolved with DATscan brain imaging of the first 4 subjects (in the phase I trial).
In addition, we would be interested to know how long the cells inside the capsules keep producing cerebrospinal fluid and other beneficial nutrients once inside the human brain. The rodent study (reviewed above) suggested reductions in production from the cells after just 6 months.
While the NTCELL capsules have been tested in many different models of neurological conditions (see the LCT’s publication page for more on this), the company suffered a set back in 2014 when they retracted one of their key pieces of research which demonstrated the use of NTCELL in a rodent model of Parkinson’s disease (Click here for more on this). The study in question was conducted by LCT between 2007 – 2009, and the results were published in The Journal of Regenerative Medicine in 2011. The study was retracted, however, because “the efficacy conclusions in the publication cannot be confirmed”.
To be fair, the company requested the retraction themselves – which is to their credit – and as a precautionary measure LCT placed a hold on any further patient recruitment in their Phase I/IIa clinical study that was underway at the time. But with this study retracted, the published preclinical research for NTCELL in Parkinson’s disease is largely limited to the primate study reviewed above (we are happy to be corrected on this).
We will be intrigued to see the results of the phase II trial, and (if all goes well) whether the New Zealand regulators will be happy for the product to be made commercially available. Depending on the results, they may request further studies. It will definitely be interesting to follow up long-term the 20 subjects who will have received the NTCELL product by that time.
We watch and wait.
UPDATE FROM 1st MAY 2017:
Today Living Cell Technologies Limited posted the following press release:
Treatment completed for all patients in Parkinson’s trial
Living Cell Technologies Limited has completed treatment of all six patients in the third and final group of patients in the Phase IIb clinical trial of NTCELL® for Parkinson’s disease, at Auckland City Hospital.
Four patients had 120 NTCELL microcapsules implanted into the putamen on each side of their brain, and two patients had sham surgery with no NTCELL implanted. To date there are no safety issues in any of the six patients.
The company is blind to the results until 26 weeks after the completion of group 3 of the trial. The results will then be analysed in accordance with the statistical plan and the conclusions announced. This is anticipated to occur in November 2017. Thereafter the patients who received the placebo will receive the optimal treatment.
The Phase IIb trial aims to confirm the most effective dose of NTCELL, define any placebo component of the response and further identify the initial target Parkinson’s disease patient sub group. Providing the trial is successful, the company will apply for provisional consent in Q4 2017 with a view to treating paying patients in New Zealand in 2018.
“The completion of treatment for the patients in group 3 brings us a step closer to our goals of obtaining provisional consent and launching NTCELL as the first disease modifying treatment for Parkinson’s disease,” says Dr Ken Taylor, CEO of Living Cell Technologies.
FULL DISCLOSURE: Living Cell Technologies Limited (LCT) is an Australasian biotechnology company that is publicly listed on the ASX and NSgene is a privately owned company. Under no circumstances should investment decisions be made based on the information provided here. In addition, SoPD has no financial or beneficial connection to either company. We have not been approached/contacted by either company to produce this post. We are simply presenting this information here following requests from our readers and because we thought the science of what the company is doing might be of interest to other readers. The author of this blog is associated with an individual contracted by LCT, but that individual did not request nor was not made aware of this post before publication.
The banner for today’s post was sourced from the Planner