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Assessing the progression of Parkinson’s is a very difficult task, but accurately doing so is critical to our ability to evaluate the disease modifying potential of new therapies.
The clinical measures currently used in clinical trials have been developed using large longitudinal studies that assessed individuals over long periods of time. But the utility of these tools have been called into question as we try to measure subtle changes in progression.
Using post-hoc (after the fact) analysis of recent clinical trial data, however, researchers have recently proposed a new method of assessment that they call “The Parkinson’s Disease Comprehensive Response” (or PDCORE).
In today’s post, we will discuss what PDCORE is and how it was identified.
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Joe Brown. Source: theBMC
I am not a climber (in fact, despite being rather tall, I am not very good at heights).
I certainly do not understand the mentality of people that need to climb mountains just to reach the top, particularly if they are simply following the same route as every other person climbing the same peak. And images of traffic jams in the “death zone” (above 8,000 meters) of Everest completely befuddle me.
Waiting for bragging rights?!? Source: NYTimes
So on the 15th April of this year when I heard about the passing of a climber named Joe Brown, I thought nothing of it… until that is, I read his story.
And more importantly his philosophy.
You see, Joe was deeply passionate about climbing and was considered one of the best by many. But for Joe it was never about getting to the top of the mountain, it was always about finding a new route up a mountain or a new way of doing something that compelled him.
Joe Brown. Source: Economist
This is a mentality I can appreciate.
It is also an idea that the Parkinson’s research community needs to embrace. If we are simply doing things because they are the way we have always done things, something is wrong.
Like Joe Brown, we need to be exploring new routes.
Which is why in today’s post we will be discussing PDCORE.
What is PDCORE?
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This week we received news of a case study involving a cell transplantation procedure that was performed during 2017/2018 on an American gentleman with Parkinson’s.
The operation (conducted in in Boston, USA) involved isolating skins cells from the individual who under went the surgery, then converting those cells into stem cells which were further encouraged to become dopamine neurons before being transplanted into his brain.
Although this is a single subject study (no control group), the result suggests that 2 years on the procedure is safe and well tolerated.
In today’s post, we will discuss the background of this research, review the published results, and explore other aspects of this story.
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On the 12th May, a story was posted on the online news site, STATnews.
I like STATnews (not an endorsement, just me sharing). They have lots of interesting stories covering a wide range of health and biotech topics.
But the story on the 12th May was different.
It focused on clinical study that involved just one participant – a gentleman from Southern California who was afflicated by Parkinson’s. He underwent a procedure called cell transplantation (Click here to read the STATnews story).
What is cell transplantation?
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The way that clinical trials are conducted doesn’t make much sense.
They take too long and a lot of resources to set up, they take a long time to be conducted, and we have to wait until they are finished before we get the results. And then on top of that we need to repeat the whole process everytime we want to make any further progress.
More efficient and adaptive models of clinical trials have been used in other medical conditions, and, thankfully, researchers are now asking if these could also be applied to Parkinson’s
In today’s post, we will discuss a recent review that explores the use of Multi-Arm Multi-Stage trial design, and asks how they could be applied to neurodegenerative conditions, like PD.
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“Mum’s the word” is a popular English idiom. It refers to not talking about a particular topic.
But where on Earth did the phrase come from?!?
In writing these blog posts, I like to try and devise clever (some might fairly say silly) titles to grab the attention of the reader. But these efforts often lead to distracting deviations of curiosity about the origins of certain quotes or titles.
“Mum’s the word” is a good example. I have used the phrase a lot in the past, but never questioned its origins. Until today that is.
The first time it appears in print is in A Walk Around London and Westminster – The Works of Mr. Thomas Brown, written in 1720 (“But Mum’s the Word – for who would speak their Mind among Tarrs and Commissioners“).
The phase, however, derives from the Latin “mimus” meaning “silent actor”, which evolved into ‘mummer’ in Old English. “Mummers” were artists who performed dances, games or plays in complete silence. Curiously this tradition is still maintained in the form of the Mummers Parade, which is held each New Year’s Day in Philadelphia:
Philadelphia Mummers Parade – doesn’t look very silent. Source: ABC
The word ‘mum’ in this context first appeared in print in William Langland’s Middle English poem “Piers Plowman” from the 1370s, and even Shakespeare has used the word ‘mum’ in his Henry VI (Part 2, Act 1, Scene 2: “Seal up your lips and give no words but mum”).
Interesting. But what has this got to do with Parkinson’s?
Like I said, it was just a silly attempt at making a cute title for this blog post.
And now, to business: Today we are going to discuss a new review exploring Multi-Arm Multi-Stage clinical trials and their potential use in Parkinson’s.
What does Multi-Arm Multi-Stage mean?
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Dyskinesias are involuntary muscle movements associated with long-term use of levodopa therapy (use of levodopa is not a certainty for developing dyskinesias, but there is an association).
A better understanding of the underlying biology of dyskinesias is required in order to alleviate this condition for those affected by it.
This week researchers reported that a single protein – called RasGRP1 – plays a central role in the development of dykinesias, raising hope that agents targeting this protein could identified and provide better quality of life of sufferers.
In today’s post, we will discuss what dyskinesias are and review the new research.
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Few people outside of the biomedical sciences may have heard of the Scripps Research Institute, but it is the largest private, not-for-profit medical research facility in the United States and among the largest in the world. It is headquartered in La Jolla, California but it has a sister facility in Jupiter, Florida.
Nice spot to do research. Source: Scripps
Collectively, “The Scripps” has 250 laboratories, which employs over 2,400 scientists, technicians, graduate students, and administrative staff.
It was founded in 1924 by journalist/philanthropist Ellen Browning Scripps.
Ellen Browning Scripps. Source: Lajollalight
The Scripps covers a wide variety of area in biomedical research, but this week a group of researcher led by scientists at the Florida Scripps institute published an interesting report on Parkinson’s:
Title: RasGRP1 is a causal factor in the development of l-DOPA–induced dyskinesia in Parkinson’s disease
Authors: Eshraghi M, Ramírez-Jarquín1 UM, Shahani1 N, Nuzzo T, De Rosa A, Swarnkar S, Galli N, Rivera O, Tsaprailis G, Scharager-Tapia C, Crynen G, Li Q, Thiolat ML, Bezard E, Usiello A, Subramaniam S
Journal: Science Advances, May 2020, 6, 18, eaaz7001
PMID: 32426479 (This report is OPEN ACCESS if you would like to read it)
In this study, the researchers were interested in proteins that could be playing a major role in the development of dyskinesias.
What are dyskinesias?
Genetic variations in a region of our DNA called PARKIN is associated with an increased risk of developing Parkinson’s – particularly young-onset PD (diagnosed before the age of 40yrs).
This area of DNA provides the instructions for making a protein (also referred to as PARKIN), which plays a number of important roles inside of cells.
Recently, a South Korean biotech company called Cellivery has published research on an experimental therapeutic agent that easily penetrates both the brain and cells within, delivering PARKIN protein to the cells that need it.
In today’s post, we will discuss what PARKIN does, review the new research report, and explore what could happen next.
Here on the SoPD we often talk about research regarding the prominent Parkinson’s associated proteins, think of alpha synuclein, LRRK2 and GBA. And they are of interest as there is a great deal of activity now at the clinical level exploring agents targetting these proteins.
But there are a number of interesting therapeutics being developed that are exploring some of the other Parkinson’s-associated proteins.
A good example was published this week:
Title: Intracellular delivery of Parkin rescues neurons from accumulation of damaged mitochondria and pathological α-synuclein
Authors: Chung E, Choi Y, Park J, Nah W, Park J, Jung Y, Lee J, Lee H, Park S, Hwang S, Kim S, Lee J, Min D, Jo J, Kang S, Jung M, Lee PH, Ruley HE & Jo D
Journal: Science Advances, 29 Apr 2020:6, 18, eaba1193
In this study, South Korean researchers demonstrated that a brain penetrating compound (including the PARKIN protein) can rescue numerous models of Parkinson’s.
Hang on a second: What is PARKIN?
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 2020.
The post is divided into seven parts based on the type of research:
So, what happened during April 2020?
In world news:
April 6th – In March, billionaire Jack Ma donated 1.1 million COVID-19 testing kits, 6 million masks and 60,000 medical use protective suits/face shields to Africa. On this date, he sent a second shipment (including 500 ventilators – source).
April 7th – Billionaire founder of Twitter, Jack Dorsey, announced he was donating $1billion (28% of his net wealth) to help fund COVID-19 relief (source).
(For more on how billionaires are supporting the COVID-19 effort – click here)
April 20th – Oil prices reached a record low (falling into negative values) due to the ongoing coronavirus pandemic and the Russia–Saudi Arabia oil price war
April 30th – Captain Tom Moore – a war veteran who has raised over £32.79 million for the NHS by completing 100 laps (25m/27yd) of his garden in 10 days – celebrated his 100th birthday
In the world of Parkinson’s research, a great deal of new research and news was reported:
In April 2020, there were 976 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (3340 for all of 2020 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 6 pieces of Parkinson’s news
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This week the outcome of an ongoing Parkinson’s clinical trial was announced.
Data collected during Part 1 of the ongoing Phase 2 PASADENA alpha synuclein immunotherapy study for Parkinson’s apparently suggests that the treatment – called prasinezumab – has not achieved it’s primary endpoint (the pre-determined measure of whether the agent has an effect in slowing Parkinson’s progression – in this case the UPDRS clinical rating scale).
But, intriguingly, the announcement did suggest ‘signals of efficacy‘ in secondary and exploratory measures.
In today’s post, we will discuss what immunotherapy is, what we know about the PASADENA study, and why no one should be over reacting to this announcement.
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At 7am on Wednesday, April 22nd, 2020, the pharmaceutical company Roche published its sales results for the 1st Quarter. This was just prior to the opening of the Swiss Stock Exchange. The financial report looked very good, particularly considering the current COVID-19 economic climate.
There was, however, one sentence on page 133 of the results that grabbed some attention:
For those of you (like myself) who struggle with fine print, the sentence reads:
“Study did not meet its primary objective, but showed signals of efficacy“
This was how the pharmaceutical giant announced the top line result of the ongoing Phase II PASADENA study evaluating the immunotherapy treatment prasinezumab in recently diagnosed individuals with Parkinson’s (listed on the Clinicaltrials.gov as NCT03100149).
At the time of publishing this SoPD post, Roche are yet to provide any further information (press release, announcement, memo, tweet, etc) regarding the results of the study.
Thankfully, a smaller biotech firm called Prothena – which is also involved in the development of the agent being tested in the Pasadena study – has kindly provided a few more details regarding these results.
In today’s post we will discuss what details have been shared in the Prothena press release regarding the Prasinezumab clinical trial in Parkinson’s (Click here to read the press release).
What is Prasinezumab?
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Parkinson’s is a neurodegenerative condition – this means that certain cells in the brain are being lost. Restorative therapies are those focused on replacing the lost cells in the hope that the new cells will be able to take up the lost function.
Tremendous efforts are being made in cell transplantation programs for Parkinson’s. But this month scientists have published a new research report proposing a novel method of changing the fate of cells already in the brain (removing the need to introduce new cells).
Their approach involves new technology and remarkably only requires the manipulation of a single protein.
In today’s post, we will explore the growing world of in vivo reprogramming, review the new research report, and discuss where in vivo reprogramming could go next.
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Changing cell fates. Source: MDPI
In vivo reprogramming of cells is a red hot topic in restorative research at the moment. The ability to change the fate of mature cells inside of an organism represents a ‘holy grail’-like goal for regenerative medicine.
Rather than transplanting ‘foreign’/external cells into the body (and having to deal with an immune system response), in vivo cellular reprogramming offers the possibility of simply changing the fate of a cell that is already present inside the body. And there are a lot of research groups around the world now exploring various methods of achieving this goal.
We have discussed the background research associated with in vivo cellular reprogramming for Parkinson’s in a previous SoPD post (Click here to read that post).
In today’s post, we are going to discuss a new research report that was published this month on this topic:
Title: Glia-to-Neuron Conversion by CRISPR-CasRx Alleviates Symptoms of Neurological Disease in Mice.
Authors: Zhou H, Su J, Hu X, Zhou C, Li H, Chen Z, Xiao Q, Wang B, Wu W, Sun Y, Zhou Y, Tang C, Liu F, Wang L, Feng C, Liu M, Li S, Zhang Y, Xu H, Yao H, Shi L, Yang H.
Journal: Cell. 2020 Apr 1. pii: S0092-8674(20)30286-5. [Epub ahead of print]
In this study, the researchers used a new technology (called CRISPR-CasRx) to reduce levels of a single protein, and the reduction of this protein appears to have aided the conversion of cells in the brains of mice to become dopamine neurons – the population of cells that are severely affected in Parkinson’s.
What is CRISPR-CasRx?
San Diego-based biotech firm Aspen Neuroscience recently announced that it has raised US$70 million in Series A funding to help its efforts to develop the first autologous neuron replacement therapy for treating Parkinson’s.
Cell replacement therapy represents a treatment approach that carries a lot of hope for the Parkinson’s community – providing new cells for the ones that have degenerated in the condition, and taking up lost function.
In today’s post, we will explore what “autologous neuron replacement therapy” means, look at what Aspen Neuroscience is doing, and discuss what will happen next.
In the SoPD ‘Road Ahead’ post at the start of this year (in which we discussed what is planned for Parkinson’s research in 2020 – click here to read that post), I briefly mentioned a biotech firm called Aspen Neuroscience.
It was one of the companies that I was going to be watching this year for signs of progress and development. I had no expectations, but was interested in what they are working on because it is in a rather exciting area of Parkinson’s research.
What does Aspen Neuroscience do?
The company works with stem cells.
It was co-founded by stem cell scientist Prof Jeanne Loring:
Prof Jeanne Loring. Source: SDT
She is a leading expert in the field of stem cell biology. Here is a video of Prof Loring talking about the potential of induced pluripotent stem cells:
What are induced pluripotent stem cells?
The results of the STEADY-PD Phase 3 clinical trial have been published. This study was evaluating the calcium channel blocker isradipine in 300 people with recently diagnosed Parkinson’s.
The results suggest that this blood pressure medication did not impact the course of the disease over the 36 months of testing (based on clinical evaluations; compared to a placebo treated group).
While this study did not reach its primary endpoint (the predetermined measure by which the treatment was assessed), a lot can be learned from this trial and it could be of interest to follow up this cohort long-term.
In today’s post, we discuss why calcium is important in Parkinson’s, explain what isradipine is, review the results of the STEADY-PD study, and explore what still could be learnt from this study.
Me and Brie. Source: Wikipedia
When I turned 25, I realised that my body no longer accepted cheese.
It had become… (how should I put this)… ‘socially embarrassing’ for me to eat cheese.
And this was a extremely serious problem.
You see, to this very day I still really like cheese.
I mean, a bottle of red wine, a baguette and a chunk of brie – is there any better combination in life?
So obviously my body and I had a falling out about the situation. And yes, it got ugly. I wanted things to keep going the way they had always been, so I tried to make things interesting with new and exotic kinds of cheeses, which my body didn’t want to know about it and simply refused to consider. It rejected all of my efforts. And after a while, I gradually started resenting my body for not letting me be who I felt I really was.
We sought help. We tried all kinds of interventions – I was really desperate, I couldn’t live without cheese. But sadly, nothing worked.
And then things went from bad to worse: My body decided that it didn’t have room in its life for yogurt, milk or even ice cream anymore (not even ice cream!!!). Basically no dairy what so ever.
Something’s missing in my life. Source: Morellisices
OMG. How did you survive without ice cream?!?