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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?
Bumetanide (Bumex) is a diuretic drug (a medication that removes water, by increasing the production of urine). It is used to treat swelling caused by heart failure or liver or kidney disease.
Recently, researchers in France have been exploring its use in Parkinson’s, and their results are really interesting.
‘Interesting’ because they not only point towards a clinically available drug that could (potentially) be repurposed for the treatments of Parkinson’s, but they also help to explain how our brains control movement.
In today’s post we will review the new results, discuss what they suggest about our ability to move, and we will look at efforts to take this drug to the clinic for Parkinson’s.
Heart failure (sometimes referred to as congestive heart failure) occurs when the heart is unable to pump sufficiently enough to maintain the required blood flow to meet the body’s needs. The most common causes of heart failure include coronary artery disease, high blood pressure, atrial fibrillation,valvular heart disease, and lifestyle issues (such as excess alcohol use). Overall around 2% of adults have heart failure; in those over the age of 65, this percentage increases to 6–10%. In 2015, it was estimated to affected approximately 40 million people worldwide (Source).
Common symptoms include:
- shortness of breath
- excessive tiredness
- leg swelling.
A common treatment option for heart failure are diuretics.
What are diuretics?
Diuretics (sometimes called water pills) are medications that have been designed to increase the amount of water and salt expelled from the body as urine.
There are three types of diuretic medications. They are:
Thiazide diuretics are the most commonly prescribed, generally for the treatment of high blood pressure. This class of drugs not only decreases the level of fluids in your body, they also cause your blood vessels to relax. Potassium-sparing diuretics reduce fluid levels in your body without – as the label suggests – causing you to lose potassium. The other types of diuretics can cause you to lose potassium, which can result in other health complications such as arrhythmia.
And then there are loop diuretics, which also decrease the level of fluid in the body.
But some loop diuretics have additional properties. And today we are going to have a look at one of them in the context of Parkinson’s.
It is called Bumetanide.
Why is Bumetanide interesting for Parkinson’s?
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?
‘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?
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).
For many people diagnosed with Parkinson’s disease, one of the scariest prospects of the condition that they face is the possibility of developing dyskinesias.
Dyskinesias are involuntary movements that can develop after long term use of the primary treatment of Parkinson’s disease: Levodopa
In todays post I discuss one experimental strategy for dealing with this debilitating aspect of Parkinson’s disease.
Dyskinesia. Source: JAMA Neurology
There is a normal course of events with Parkinson’s disease (and yes, I am grossly generalising here).
First comes the shock of the diagnosis.
This is generally followed by the roller coaster of various emotions (including disbelief, sadness, anger, denial).
Then comes the period during which one will try to familiarise oneself with the condition (reading books, searching online, joining Facebook groups), and this usually leads to awareness of some of the realities of the condition.
One of those realities (especially for people with early onset Parkinson’s disease) are dyskinesias.
What are dyskinesias?
Dyskinesias (from Greek: dys – abnormal; and kinēsis – motion, movement) are simply a category of movement disorders that are characterised by involuntary muscle movements. And they are certainly not specific to Parkinson’s disease.
As I have suggested in the summary at the top, they are associated in Parkinson’s disease with long-term use of Levodopa (also known as Sinemet or Madopar).
Sinemet is Levodopa. Source: Drugs
In December, we highlighted the results of a phase 1 clinical trial for Parkinson’s disease being run by a company called Voyager Therapeutics (Click here for that post). In that post we also explained that the company is attempting to take a gene therapy product (VY-AADC01) to the clinic.
VY-AADC01 is a virus that is injected into a particular part of the brain (called the putamen), where it infects cells in that area and causes them to produce a lot of a particular protein, called Aromatic L-amino acid decarboxylase (or AADC). AADC is required for turning L-dopa (one of the primary treatments for Parkinson’s disease) into dopamine – which helps to ease the motor features of the condition.
Today, while most people were focused on President Trump’s inauguration, Voyager Therapeutics provided an update on their ongoing trials. Specifically, the company reported an increase in viral infection coverage of the putamen was achieved by VY-AADC01 in their third group (‘cohort’) of subjects. They infected 42% of the putamen compared to 34% in group 2 and 21% in group 1.
In the press release, the company stated:
“The five patients enrolled in Cohort 3 received similar infusion volumes of VY-AADC01 compared to Cohort 2 (up to 900 µL per putamen), but three-fold higher vector genome concentrations, representing up to a three-fold higher total dose of up to 4.5×1012 vector genomes (vg) of VY-AADC01 compared to patients in Cohort 2 (1.5 × 1012 vg). Patients enrolled in Cohort 3 were similar in baseline characteristics to Cohort 1 and 2. The use of real-time, intra-operative MRI-guided delivery allowed the surgical teams to visualize the delivery of VY-AADC01 and continue to achieve greater average coverage of the putamen in Cohort 3 (42%) compared to Cohort 2 (34%) with similar infusion volumes and Cohort 1 (21%) with a lower infusion volume (Figure 1). The surgical procedure was successfully completed in all five patients. Infusions of VY-AADC01 have been well-tolerated with no vector-related serious adverse events (SAEs) or surgical complications in Cohort 3, and all five patients were discharged from the hospital within two days following surgery. The Phase 1b trial remains on track to deliver six-month safety, motor function, and biomarker data from Cohort 3, as well as longer-term safety and motor function data from Cohorts 1 and 2, in mid-2017.”
This update demonstrates that the company is proceeding with increased concentrations of their virus, resulting in a wider area of the putamen being infected and producing AADC. Whether this increased area of AADC producing cells results in significant improvements to motor features of Parkinson’s disease, we shall hopefully begin to find out later this year.
As always, watch this space.
Exciting new last week from a small biotech company called Voyager Therapeutics which is using gene therapy to treat neurodegenerative disease. Their primary product (VY-AADC01) is focused on Parkinson’s disease and the initial results look very positive.
The press release has indicates that the treatment is well tolerated and has beneficial effects on the subject’s motor functions. This last part is very interesting as the trial is being conducted on people with advanced Parkinson’s disease.
In today’s post, we’ll review the technology and what the results mean.
Gene therapy. Source: HuffingtonPost
In Parkinson’s disease, we often talk about the loss of the dopamine neurons in the midbrain as a cardinal feature of the disease. When people are diagnosed with Parkinson’s disease, they have usually lost approximately 50-60% of the dopamine neurons in an area of the brain called the substantia nigra.
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source: Memorangapp
The midbrain is – as the label suggests – in the middle of the brain, just above the brainstem (see image below). The substantia nigra dopamine neurons reside there.
Location of the substantia nigra in the midbrain. Source: Memorylossonline
The dopamine neurons of the substantia nigra generate dopamine and release that chemical in different areas of the brain. The primary regions of that release are areas of the brain called the putamen and the Caudate nucleus. The dopamine neurons of the substantia nigra have long projections (or axons) that extend a long way across the brain to the putamen and caudate nucleus, so that dopamine can be released there.
The projections of the substantia nigra dopamine neurons. Source: MyBrainNotes
In Parkinson’s disease, these ‘axon’ extensions that project to the putamen and caudate nucleus gradually disappear as the dopamine neurons of the substantia nigra are lost. When one looks at brain sections of the putamen after the axons have been labelled with a dark staining technique, this reduction in axons is very apparent over time, especially when compared to a healthy control brain.
The putamen in Parkinson’s disease (across time). Source: Brain
Previously we have discussed replacing the loss dopamine by transplanting dopamine producing cells into the putamen (click here to read that post), but some researchers now believe that this is not necessary. Instead they have proposed using gene therapy for Parkinson’s disease.
What is gene therapy?
The gene therapy involves inducing cells to produce proteins that they usually do not. This is usually done using genetically modified viruses which have had all the disease causing component removed, allowing us to use the virus as an efficient delivery system. Viruses by their very nature are very good at infecting cells, so if we remove the disease causing components, what is left is a very effective delivery system. Taking this approach one step further, we could next take genes involved with dopamine synthesis and insert them into our empty virus. By then injecting this virus into the brain, we could produce dopamine in any infected cells (it’s slightly more complicated than that, but you get the basic idea).
Gene therapy for Parkinson’s disease. Source: Wiki.Epfl
This approach demonstrated amazing results in preclinical studies in the lab, but the transition to the clinic has not been easy (click here for a good review of the field).
What has been done in the clinic for gene therapy and Parkinson’s disease?
The first clinical attempt at gene therapy for Parkinson’s disease involved injecting a virus containing a gene called glutamic acid decarboxylase (GAD), which is an enzyme involved in the production of a chemical called GABA. The virus was injected into an area of the brain called the subthalamic nucleus, which becomes over-active in Parkinson’s disease. By ectopically producing GAD in the subthalamic nucleus, researchers were able to reduce the level of activity (this is similar to deep brain stimulation in Parkinson’s disease which modulates the activity of the subthalamic nucleus). The clinical trials for GAD produced modest results. The virus was well tolerated, but the clinical effect was limited.
Another clinical trial attempted to cause cells in the putamen to produce a chemical called neurturin (which is very similar to GDNF – we have previously written about GDNF, click here to read that post). The goal of the study was to prove neuroprotection and regeneration to the remaining dopamine neurons, by releasing neurturin in the putamen. Subjects were injected in the putamen with the virus and then the participants were followed for 15 months. Unfortunately, this study failed to demonstrate any meaningful improvement in subjects with Parkinson’s disease.
So what were the results of the trial?
Voyager Therapeutics‘s gene therapy product, VY-AADC01 is an adeno associated virus that carries a gene called Aromatic L-amino acid decarboxylase (or AADC).
AAV Viruses. Source: HuffingtonPost
Yeah, I know: what is AADC?
AADC is the enzyme that converts L-dopa into dopamine. L-dopa can be naturally produced in the brain from Tyrosine that is absorbed from the blood. It is also the basic component of many treatments for Parkinson’s disease.
The production of dopamine. Source: Slideplayer
By injecting VY-AADC01 into the putamen of people with advanced Parkinson’s disease, Voyager is hoping to alleviate the motor features of the condition by allowing the brain to produce a constant supply of dopamine in the exact location that is missing the dopamine (remember, the putamen is where dopamine is released). This approach will not cure the disease, but it may make life a lot easier for those affected by it.
The phase 1b clinical trial was designed to assess whether the virus had any negative side effects in humans. After the subjects were injected in the brain with VY-AADC01, they were assessed at six and twelve months after the surgery. The results suggest that the virus was well tolerated and resulted in increased AADC enzyme activity, enhanced response to L-dopa treatment, and clinically meaningful improvements in various measures of patients’ motor function (44% improvement in ‘off medication’ measures and 55% improvement in ‘on medication’ measures).
The company currently has 2 groups of subjects injected with the virus (two different concentrations) and they are looking to have a third group injected in early 2017. Phase 2 trials are planned to begin in late 2017.
What does it all mean?
They are also interesting results because the subjects involved in the study all have advanced Parkinson’s disease (the average time since diagnosis in the subject was 10 years). So it is very positive news to see beneficial effects in later stage subjects.
Our ability to delivery of genes to different locations is a symbol of how far we have come with our understanding of biology. The fact that this knowledge is now having a positive impact in the medical world is very exciting. Gene therapy is one treatment approach that we here at SoPD are very excited about and watching very closely.
The banner for today’s post was sourced from Voyager Therapeutics