Over the last 12 months, the Silverstein Foundation has quickly established itself as a major focused force in the fight against Parkinson’s.
And when I say ‘focused’, I mean ‘focused’ – the foundation is “actively pursues and invests in cutting edge research with the goal of discovering new therapies for the treatment of Parkinson’s Disease in glucocerebrosidase (GBA) mutation carriers”.
But the output of this effort may well have major benefits for the entire Parkinson’s community.
In today’s post, we will discuss what GBA is, how it functions inside cells, its association with Parkinson’s, and what all of this GBA focused research being funded by the Silverstein Foundation could mean for the Parkinson’s community.
Jonathan Silverstein. Source: Forbes
This is Jonathan Silverstein.
He’s a dude.
He is also a General Partner and a Co-Head of Global Private Equity at OrbiMed – the world’s largest fully dedicated healthcare fund manager. During his time at OrbiMed, the company has invested in healthcare companies that have been involved with over 60 FDA approved products.
In February 2017, he was diagnosed with Parkinson’s disease at just 49 years of age.
Rather than simply accepting this diagnosis, however, Mr Silverstein decided to apply the skills that he has built over a long and successful career in funding biotech technology, and in March 2017, he and his wife, Natalie, set up the Silverstein Foundation.
They raised $6 million from donors and then provided another $10 million of their own money to fund the endeavour, which has funded a dozen research projects and started a new company called Prevail Therapeutics (we’ll come back to this shortly).
The foundation has just one mission: “to actively pursue and invest in cutting edge research with the goal of discovering new therapies for the treatment of Parkinson’s Disease in GBA mutation carriers”
And it seeks to address this by achieving three goals:
- to find a way to halt the progression of Parkinson’s with GBA.
- to identify regenerative approaches to replace the damaged/lost cells
- to find preventative measures
What is ‘GBA’?
Today biotech company Voyager Therapeutics announced an update on their ongoing phase Ib clinical trial. The trial is evaluating the safety and tolerance of a gene therapy approach for people with advanced Parkinson’s.
Gene therapy is a technique that involves inserting new DNA into a cell using viruses. In this clinical trial, the virally delivered DNA helps the infected cell to produce dopamine in order to alleviate the motor features of Parkinson’s.
In today’s post we will discuss what gene therapy is, review the new results mentioned in the update, and look at other gene therapy approaches for Parkinson’s.
Voyager Therapeutics is a clinical-stage gene therapy company that is focused on treatments for neurological conditions, such as Parkinson’s. Today the company announced an update of their ongoing Phase 1b trial of their product VY-AADC01 (Click here to see the press release).
VY-AADC01 represents a new class of treatment for Parkinson’s, as it is a form of gene therapy.
What is gene therapy?
The gene therapy involves introducing a piece of DNA into a cell which will cause the cell to produce proteins that they usually do not (either by nature or by mutation). The DNA is artificially inserted into cells and the cell’s protein producing machinery does the rest.
How does gene therapy work?
Each time a cell divides, the DNA inside the resulting pair of cells has changed slightly. These small alterations – known as genetic mutations – provide a method by which an organism can randomly determine traits that may be beneficial.
New research indicates that in certain parts of the brain, post-mitotic (non-dividing) cells are taking on as many as one mutation per week across the span of our lives. This results in thousands of genetic variations accumulating in each cell by the time we eventually pass away in old age.
In today’s post we will review new research and consider what this gradual build up of genetic mutations could mean for our understanding of neurodegenerative conditions, like Parkinson’s.
Coming from the back waters of third world New Zealand, you will understand that sheep hold a very special place in my heart.
I grew up a simple country lad, and each year I had a pet lamb that I would raise and train to do silly tricks in the hope of impressing the judges at the annual agricultural/farm day at school. In addition to instilling me with a crazy fanaticism for the sport (read: religion) of rugby, my parents figured that having a pet lamb each year would teach me a sense of responsibility and a sort of discipline.
I’m not really sure how this practice has influenced my later life, but I certainly do have very fond memories of those early years (the first lamb was named ‘Woolly’, the 2nd lamb was named ‘Woolly2’, the third lamb was actually a goat – bad lambing season – which I named ‘Billy the kid’, the 4th lamb was named ‘MacGyver’,…).
Lots of happy memories.
But as I grew into the teenage years, there was one thing that really bothered me with regards to my pet lambs.
It was that whole negative stigma associated with the ‘black sheep’.
Why, I would wonder, was it the ‘black sheep of the family’ that was the bad kid? And why was the one black sheep in every flock considered the worst of the bunch?
Why was this association applied to sheep?
Why not dogs? Or cows? Why do we pick on sheep?
‘Parkinsonisms’ refer to a group of neurological conditions that cause movement features similar to those observed in Parkinson’s disease. They include multiple system atrophy (MSA) and Progressive supranuclear palsy (PSP) and idiopathic Parkinson’s.
Newly published research now shines a light on a possible mechanism for differentiating between multiple system atrophy and idiopathic Parkinson’s.
In today’s post we will look at what multiple system atrophy is, review the new research report, and discuss what these results could mean for the Parkinson’s community.
Brain immaging of multiple system atrophy–related spatial covariance pattern (MSARP) and Parkinson disease–related spatial covariance pattern (PDRP). Source: Neurology
For a long time I have been looking to write a piece of Multiple system atrophy.
I have been contacted by several readers asking for more information about it, and the only thing really delaying me – other than the tsunami of Parkinson’s related research that I am currently trying to write posts for – was the lack of a really interesting piece of research to base the post around.
Guess what came into my inbox yesterday:
Title: Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication.
Authors: Woerman AL, Kazmi SA, Patel S, Aoyagi A, Oehler A, Widjaja K, Mordes DA, Olson SH, Prusiner SB.
Journal: Proc Natl Acad Sci U S A. 2017 Dec 26. pii: 201719369.
This is a really interesting piece of research, that continues a line of other really interesting research.
And if it is independently replicated and verified, it will have massive implications for the Parkinson’s community, particularly those affected by Multiple System Atrophy.
But before we deal with that, let’s start with the obvious question:
What is Multiple System Atrophy?
Last week, as everyone was preparing for Christmas celebrations, researchers at the pharmaceutic company Novartis published new research on a gene that is involved with Parkinson’s, called PARKIN (or PARK2).
They used a new gene editing technology – called CRISPR – to conduct a large screening study to identify proteins that are involved with the activation of PARKIN.
In today’s post we will look at what PARKIN does, review the research report, and discuss how these results could be very beneficial for the Parkinson’s community.
As many people within the Parkinson’s community will be aware, 2017 represented the 200th anniversary of the first report of Parkinson’s disease by James Parkinson.
It also the 20th anniversary of the discovery of first genetic mutation (or variant) that increases the risk of developing Parkinson’s. That genetic variation occurs in a region of DNA (a gene) called ‘alpha synuclein’. Yes, that same alpha synuclein that seems to play such a critical role in Parkinson’s (Click here to read more about the 20th anniversary).
In 2018, we will be observing the 20th anniversary of the second genetic variation associated with Parkinson.
That gene is called PARKIN:
Title: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.
Authors: Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N
Journal: Nature. 1998 Apr 9; 392(6676):605-8
In 1998, Japanese researchers published this report based on 5 individuals from 4 Japanese families who were affected by juvenile-onset Parkinson’s. In family 1, the affected individual was a female, 43 years old, born of first-cousin parents, and her two younger brothers are healthy. Her condition was diagnosed in her teens and it had then progressed very slowly afterwards. Her response to L-dopa was very positive, but L-dopa-induced dyskinesia were frequent. In family 2-4, affected individuals (born to unrelated parents) exhibited very similar clinical features to the subject in family 1. The age of onset was between 18 to 27 years of age.
Using previous research and various techniques the investigators were able to isolate genetic variations that were shared between the 5 affected individuals. They ultimately narrowed down their search to a section of DNA containing 2,960 base pairs, which encoded a protein of 465 amino acids.
They decided to call that protein PARKIN.
PARKIN Protein. Source: Wikipedia
How much of Parkinson’s is genetic?
Gene therapy involves treating medical conditions at the level of DNA – that is, altering or enhancing the genetic code inside cells to provide therapeutic benefits rather than simply administering drugs. Usually this approach utilises specially engineered viruses to deliver the new DNA to particular cells in the body.
For Parkinson’s, gene therapy techniques have all involved direct injections of these engineered viruses into the brain – a procedure that requires brain surgery. This year, however, we have seen the EXTREMELY rapid development of a non-invasive approach to gene therapy for neurological condition, which could ultimately see viruses being injected in the arm and then travelling up to the brain where they will infect just the desired population of cells.
Last week, however, this approach hit a rather significant obstacle.
In today’s post, we will have a look at this gene therapy technology and review the new research that may slow down efforts to use this approach to help to cure Parkinson’s.
Gene therapy. Source: rdmag
When you get sick, the usual solution is to visit your doctor.
They will prescribe a medication for you to take, and then all things going well (fingers crossed/knock on wood) you will start to feel better. It is a rather simple and straight forward process, and it has largely worked well for most of us for quite some time.
As the overall population has started to live longer, however, we have begun to see more and more chronic conditions which require long-term treatment regimes. The “long-term” aspect of this means that some people are regularly taking medication as part of their daily lives. In many cases, these medications are taken multiple times per day.
A good example of this is Levodopa (also known as Sinemet or Madopar) which is the most common treatment for the chronic condition of Parkinson’s disease.
When you swallow your Levodopa pill, it is broken down in the gut, absorbed through the wall of the intestines, transported to the brain via our blood system, where it is converted into the chemical dopamine – the chemical that is lost in Parkinson’s disease. This conversion of Levodopa increases the levels of dopamine in your brain, which helps to alleviate the motor issues associated with Parkinson’s disease.
Levodopa. Source: Drugs
This pill form of treating a disease is only a temporary solution though. People with Parkinson’s – like other chronic conditions – need to take multiple tablets of Levodopa every day to keep their motor features under control. And long term this approach can result in other complications, such as Levodopa-induced dyskinesias in the case of Parkinson’s.
Yeah, but is there a better approach?
Recently a Parkinson’s-associated research report was published that was the first of many to come.
It involves the use of a genetic screening experiment that incorporates new technology called ‘CRISPR’.
There is an absolute tidal wave of CRISPR-related Parkinson’s disease research coming down the pipe towards us, and it is important that the Parkinson’s community understands how this powerful technology works.
In today’s post we will look at what the CRISPR technology is, how it works, what the new research report actually reported, and discuss how this technology can be used to tackle a condition like Parkinson’s.
Me and my mother (and yes, the image is to scale). Source: Openclipart
My mother: Simon, what is all this new ‘crispy’ research for Parkinson’s I heard about on the news?
Me: Huh? (I was not really paying attention to the question. Terrible to ignore one’s mother I know, but what can I say – I am the black sheep of the family)
My mother: Yes, something about ‘crispy’ and Parkinson’s.
Me: Oh! You mean CRISPR. Yeah, it’s really cool stuff.
My mother: Ok, well, can you explain it all to me please, this ‘Crisper’ stuff?
CRISPR.101 (or CRISPR for beginners)
In almost every cell of your body, there is a nucleus.
It is the command centre for the cell – issuing orders and receiving information concerning everything going on inside and around the cell. The nucleus is also a storage bank for the genetic blueprint that provides most of the instructions for making a physical copy of you. Those grand plans are kept bundled up in 23 pairs of chromosomes, which are densely coiled strings of a molecule called Deoxyribonucleic acid (or DNA).
DNA’s place inside the cell. Source: Kids.Britannica
This week a biotech company called Voyager Therapeutics announced the results of their ongoing phase Ib clinical trial. The trial is investigating a gene therapy approach for people with severe Parkinson’s disease.
Gene therapy is a technique that involves inserting new DNA into a cell using a virus. The DNA can help the cell to produce beneficial proteins that go on help to alleviate the motor features of Parkinson’s disease.
In today’s post we will discuss gene therapy, review the new results and consider what they mean for the Parkinson’s community.
On 25th August 2012, the Voyager 1 space craft became the first human-made object to exit our solar system.
After 35 years and 11 billion miles of travel, this explorer has finally left the heliosphere (which encompasses our solar system) and it has crossed into the a region of space called the heliosheath – the boundary area that separates our solar system from interstellar space. Next stop on the journey of Voyager 1 will be the Oort cloud, which it will reach in approximately 300 years and it will take the tiny craft about 30,000 years to pass through it.
Where is Voyager 1? Source: Tampabay
Where is Voyager actually going? Well, eventually it will pass within 1 light year of a star called AC +79 3888 (also known as Gliese 445), which lies 17.6 light-years from Earth. It will achieve this goal on a Tuesday afternoon in 40,000 years time.
Gliese 445 (circled). Source: Wikipedia
Remarkably, the Gliese 445 star itself is actually coming towards us. Rather rapidly as well. It is approaching with a current velocity of 119 km/sec – nearly 7 times as fast as Voyager 1 is travelling towards it (the current speed of the craft is 38,000 mph (61,000 km/h).
Interesting, but what does any of that have to do with Parkinson’s disease?
Well closer to home, another ‘Voyager’ is also ‘going boldly where no man has gone before’ (sort of).
One of the most common observations that people make when they attend a Parkinson’s disease support group meeting is the huge variety of symptoms between sufferers.
Some people affected by this condition are more tremor dominant, while others have more pronounced gait (or walking) issues. In addition, some people have an early onset version, while others has a very later onset. What could explain this wide range of features?
A group of Stanford researchers have recently proposed an interesting new idea regarding our understanding of genetics that could partly explain some of this variability. In todays post I speculate on whether their idea could be applied to Parkinson’s disease.
Earlier this year an interesting study was published in the prestigious journal Nature on the topic of the genetics of height (yes height. Trust me, I’m going somewhere with this):
Title: Rare and low-frequency coding variants alter human adult height
Authors: Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR, Kjaer TR, Fine RS, Lu Y, Schurmann C,………at least 200 additional authors have been deleted here in order to save some space…….EPIC-InterAct Consortium; CHD Exome+ Consortium; ExomeBP Consortium; T2D-Genes Consortium; GoT2D Genes Consortium; Global Lipids Genetics Consortium; ReproGen Consortium; MAGIC Investigators, Rotter JI, Boehnke M, Kathiresan S, McCarthy MI, Willer CJ, Stefansson K, Borecki IB, Liu DJ, North KE, Heard-Costa NL, Pers TH, Lindgren CM, Oxvig C, Kutalik Z, Rivadeneira F, Loos RJ, Frayling TM, Hirschhorn JN, Deloukas P, Lettre G.
Journal: Nature. 2017 Feb 9;542(7640):186-190.
In this study, the researchers – who are part of the GIANT consortium – were analysing DNA collected from over 700,000 people and trying to determine what genetic differences could influence height.
Height is not important for music. Source: Imgur
Why study height?
Good question. There are several reasons:
Firstly, it is easy to accurately measure. Second, the researchers believed that if we can master the complex genetics of something simple like height maybe what we learn will give us a blueprint for how we should study more complex medical disorders that have thus far eluded our complete understanding.
On the 27th June, 1997, a research report was published in the prestigious scientific journal ‘Science’ that would change the world of Parkinson’s disease research forever.
And I am not exaggerating here.
The discovery that genetic variations in a gene called alpha synuclein could increase the risk of developing Parkinson’s disease opened up whole new areas of research and eventually led to ongoing clinical trials of potential therapeutic applications.
Todays post recounts the events surrounding the discovery, what has happened since, and we will discuss where things are heading in the future.
It is fair to say that 1997 was an eventful year.
In world events, President Bill Clinton was entering his second term, Madeleine Albright became the first female Secretary of State for the USA, Tony Blair became the prime minister of the UK, and Great Britain handed back Hong Kong to China.
#42 – Bill Clinton. Source: Wikipedia
In the world of entertainment, author J. K. Rowling’s debut novel “Harry Potter and the Philosopher’s Stone” was published by Bloomsbury, and Teletubbies, South Park, Ally McBeal, and Cold Feet (it’s a British thing) all appeared on TV for the first time, amusing and entertaining the various age groups associated with them.
South Park. Source: Hollywoodreporter
Musically, rock band Blur released their popular hit song ‘Song 2‘ (released 7th April), “Bitter Sweet Symphony” by the Verve entered the UK charts at number 2 in June, and rapper Notorious B.I.G. was killed in a drive by shooting. Oh, and let’s not forget that “Tubthumping” (also known as “I Get Knocked Down”) by Chumbawamba was driving everybody nuts for its ubiquitous presence.
And at the cinemas, no one seemed to care about anything except a silly movie called Titanic.
Titanic. Source: Hotspot
Feeling old yet?