Tagged: GDNF

Are we getting NURR to the end of Parkinson’s disease?

Nuclear receptor related 1 protein (or NURR1) is a protein that is critical to the development and survival of dopamine neurons – the cells in the brain that are affected in Parkinson’s disease.

Given the importance of this protein for the survival of these cells, a lot of research has been conducted on finding activators of NURR1.

In today’s post we will look at this research, discuss the results, and consider issues with regards to using these activators in Parkinson’s disease.


Comet Hale–Bopp. Source: Physics.smu.edu

Back in 1997, 10 days after Comet Hale–Bopp passed perihelion (April 1, 1997 – no joke; perihelion being the the point in the orbit of a comet when it is nearest to the sun) and just two days before golfer Tiger Woods won his first Masters Tournament, some researchers in Stockholm (Sweden) published the results of a study that would have a major impact on our understanding of how to keep dopamine neurons alive.

Dopamine neurons are one group of cells in the brain that are severely affected by Parkinson’s disease. By the time a person begins to exhibit the movement symptoms of the condition, they will have lost 40-60% of the dopamine neurons in a region called the substantia nigra. In the image below, there are two sections of brain – cut on a horizontal plane through the midbrain at the level of the substantia nigra – one displaying a normal compliment of dopamine neurons and the other from a person who passed away with Parkinson’s demonstrating a reduction in this cell population.

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The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp

The researchers in Sweden had made an amazing discovery – they had identified a single gene that was critical to the survival of dopamine neurons. When they artificially mutated the section of DNA where this gene lives – an action which resulted in no protein for this gene being produced – they generated genetically engineered mice with no dopamine neurons:

Title: Dopamine neuron agenesis in Nurr1-deficient mice
Authors: Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T.
Journal: Science. 1997 Apr 11;276(5310):248-50.
PMID: 9092472

The researchers who conducted this study found that the mice with no NURR1 protein exhibited very little movement and did not survive long after birth. And this result was very quickly replicated by other research groups (Click here and here to see examples)

So what was this amazing gene called?

Continue reading

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Voyager Therapeutics: phase Ib clinical trial results

 

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.


Source: Joshworth

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).

Continue reading

Future of gene therapy: hAAVing amazing new tools

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In this post I review recently published research describing interesting new gene therapy tools.

“Gene therapy” involved using genetics, rather than medication to treat conditions like Parkinson’s disease. By replacing faulty sections of DNA (or genes) or providing supportive genes, doctors hope to better treat certain diseases.

While we have ample knowledge regarding how to correct or insert genes effectively, the problem has always been delivery: getting the new DNA into the right types of cells while avoiding all of the other cells.

Now, researchers at the California Institute of Technology may be on the verge of solving this issue with specially engineered viruses.



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Gene therapy. Source: yourgenome

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 become more and more exposed to 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.

An 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.

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Levodopa. Source: Drugs

This pill form of treating a disease is only a temporary solution though. People with Parkinson’s disease – 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?

Some researchers believe there is. But we are not quite there yet with the application of that approach. Let me explain:

Continue reading

Gene therapy in Parkinson’s disease

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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.


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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.

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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.

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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.

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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.

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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).

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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).

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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.

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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?

Well, this is a very interesting result and bodes well for other companies taking similar gene therapy approaches (these include Oxford BioMedica and Genepod Therapeutics).

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

The GDNF trial (Bristol) initial results

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We learned today that the phase 2 GDNF clinical trial in Bristol (UK) has failed to meet the primary efficacy end point. That is to say, the initial results suggest that the drug has not worked. In this post we will review what we know and discuss what will happen next.


infusion1

GDNF was pumped into the striatum (green area). Source: Bankiewicz lab

We have previously discussed GDNF and Parkinson’s disease (Click here to read that post). This drug was considered the great hope for Parkinson’s disease and a lot was riding on the results. Today’s announcement is extremely unwelcomed news, but it is not necessarily the end of the road for GDNF.

What is GDNF?

Glial cell-derived neurotrophic factor (or GDNF) is a neurotrophic factor (neurotrophic = Greek: neuron – nerve; trophikós – pertaining to food/to feed). It is a chemical produced in the brain. GDNF has previously been found to have miraculous effects on some of the neurons in the brain that are most affected by Parkinson’s disease (particularly the dopamine neurons).

Given the amazing results in laboratories around the world, clinical trials were set up for people with Parkinson’s disease. The first study had astounding results, but a larger follow up study failed to replicate those results and so a third GDNF clinical trial was initiated: the Bristol GDNF study

What is the Bristol GDNF study?

The Bristol GDNF study run by the the North Bristol NHS Trust, was funded by Parkinson’s UK, with support from The Cure Parkinson’s Trust. The company MedGenesis Therapeutix supplied the GDNF and additional project resources/funding. MedGenesis Therapeutix itself has funding support from the Michael J. Fox Foundation for Parkinson’s Research.

The study involved participants having GDNF (or a placebo drug) pumped directly into their brains, into an area called the putamen. The putamen is where the greatest loss of dopamine occurs in people with Parkinson’s disease.

All together there were 41 people with Parkinson’s disease enrolled in the clinical trial. The trial was divided into two phases and the first of those is now complete. During the first phase 35 participants received either GDNF or a placebo drug over 9-months in a double blind fashion

What does double blind mean?

It means that neither the researchers nor the participants know which drug they are receiving. Everyone is ‘blind’ to the treatment. Single blind studies involve the researchers being aware of the treatment allocation, but the participants are blind. Single blind studies can be affected by what is called ‘investigator bias’ – where the investigators start to think that they see an effect when there may not be an effect. Double blind is considered the gold standard, but there are problems with this type of study as well.

If phase one has finished what is phase two of the trial?

The second phase of the study will involve all participants receiving GDNF. This part is already underway.

What was the “primary efficacy end point”?

The press release from the company behind the study, MedGenesis, suggested that:

‘The primary endpoint of the study is the percentage change from baseline in the practically defined OFF-state Unified Parkinson’s Disease Rating Scale (UPDRS) motor score (part III) after nine months of double-blind treatment’

With the limited information we currently have, we are assuming that the researchers were looking for a significant improvement in the motor symptoms rating scale (‘UPDRS’) of the subjects when compared to how they were at the start of the trial (‘baseline’). The subject’s motor features were assessed during periods when they were not taking their medication (‘OFF-state’), and the initial indications are that the researchers failed to see any improvement.

Is this negative result the end of the world?

NO. Most definitely not.

There are many reasons why the trial may have failed to achieve its primary end point, and the researchers have emphasized that they need time to analyse all of the results. It will be interesting to see the final analysis (and we will summarise it here when it is available – end of 2016 apparently).

It will also be important to follow up the participants to determine if there are any delayed positive outcomes. It may take longer than 9 months to see improvements (fetal transplant studies, for example, usually require 2-3 years before improvements are observed).

 

Maybe GDNF just needs a bit more time. We will keep you updated as more information comes to hand.


For more on the study, please see Parkinson’s UK and MedGenesis.

GDNF and Parkinson’s disease

In 1991, Leu-Fen Lin and Frank Collins – both research scientists at a small biotech company in Boulder, Colorado – isolated a protein that was going to have an enormous impact on experimental therapeutic approaches for Parkinson’s disease over the next two decades. The company was called Synergen, and the protein they discovered was glial cell-derived neurotrophic factor, or GDNF.

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The structure of GDNF. Source: Wikipedia

A great deal has been written about GDNF and Parkinson’s disease (there are some very good books on the story of the development of GDNF as a drug), here we will provide an overview and look at what is currently happening.

So what is GDNF?

Glial cells are the support cells in the brain. From the Greek γλία and γλοία meaning “glue”, glial cells make up more than 50% percentage of the total number of cells in the brain – though this ratio can vary across different regions.

Glial_Cells

Large neurons supported by smaller glial cells. Source: Scientific Brains

Glials cells look after the ‘work horses’ – the neurons – by maintaining the environment surrounding the neurons and supplying them with supportive chemicals, called neurotrophic factors (neurotrophic = Greek: neuron – nerve; trophikós – pertaining to food/to feed). There are many types of neurotrophic factors, some having more beneficial effects on certain types of neurons and not other. GDNF is one of these neurotrophic factors. It was isolated from a cell culture of rat glial cells (hence the name: glial cell-derived neurotrophic factor), and what became clear very quickly after it’s discovery was that it dramatically revived dying dopamine neurons (the cells classically affected in Parkinson’s disease). Leu-Fen Lin and Frank Collins’s initial results were astounding and they were published in 1993. Many studies in animal models of Parkinson’s disease followed and in almost all of those studies the results were amazing (here is a good review of the early literature).

GDNF is a member of a larger family of neurotrophic factors and three other members of that family (called neurturin, persephin, and artemin – sounds like the Three Musketeers!) have also demonstrated positive effects on dying dopamine neurons. The positive/neuroprotective effect works via a series of receptors on the surface of cells. There a receptors that are specific for each of the GDNF family members discussed above:

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The GDNF family. Source: Nature

And they each exert their positive affect in combination with a protein called ret proto-oncogene (RET). RET is a receptor tyrosine kinase, which is a cell-surface molecule that initiates signals inside the cell resulting in cell growth and survival. Dopamine neurons have most of these receptors and a lot of RET.

What has happened with GDNF in the clinic?

Given the results of the initial studies with GDNF (and its family members), clinical studies/trials were set up to test if similar effects would be seen in humans.

The very first clinical trial pumped GDNF into the fluid surrounding the brain, but the drug did not penetrate very deep into the brain and had limited effect. One side effect of the treatment was a hyper-sensitivity to pain (called hyperalgesia) – patients literally couldn’t tolerate the clothes touching their bodies.

This initial failure gave rise to another clinical study at the Frenchay Hospital in Bristol (UK) in which GDNF was released inside the brain, in an area called the striatum. Tiny plastic tubes were implanted in the brain allowing for the GDNF to be pumped in.

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GDNF was pumped into the striatum (green area). Source: Bankiewicz lab

Although the number of subjects in the study was very small (only 5 people with Parkinson’s), the results of that particular study were simply amazing.

GDNFtitle1

Title: Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease.
Authors: Gill SS, Patel NK, Hotton GR, O’Sullivan K, McCarter R, Bunnage M, Brooks DJ, Svendsen CN, Heywood P.
Journal: Nat Med. 2003 May;9(5):589-95.
PMID: 12669033

The researchers reported that after just one year of GDNF treatment, there was:

  • a 39% improvement in the off-medication motor ability (according to the Unified Parkinson’s Disease Rating Scale (UPDRS))
  • a 61% improvement in how subjects perceived their ability to go about daily activities.
  • a 64% reduction in medication-induced dyskinesias (and they were not observed off medication)
  • no serious clinical side effects

Importantly, the researchers conducted brain imaging studies on the subjects and a 28% increase in striatum dopamine storage after 18 months.

And that study was followed up by an outcome report two years later, which had similar results.

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Title: Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study.
Authors: Patel NK, Bunnage M, Plaha P, Svendsen CN, Heywood P, Gill SS.
Journal: Ann Neurol. 2005 Feb;57(2):298-302.
PMID: 15668979

And then the researchers published a case study of one patient, suggesting that the positive effects of GDNF were still having an impact 3 years after the drug had stopped being delivered:

Title: Benefits of putaminal GDNF infusion in Parkinson disease are maintained after GDNF cessation.
Authors: Patel NK, Pavese N, Javed S, Hotton GR, Brooks DJ, Gill SS.
Journal: Neurology. 2013 Sep 24;81(13):1176-8.
PMID: 23946313

 

There were two issues with this initial GDNF pump study however:

  1. The trial was open label. Both the subjects taking part and the physicians running the study knew who was getting the drug. The study was not blind.
  2. A larger double blind study did not find the same results.

The Amgen “Double-Blind” Trial

In 2003, based on the Bristol study results, the pharmaceutical company Amgen (which owned GDNF) initiated a double blind clinical trial for GDNF with 34 patients. Being double blind, both the researchers and the participants did not know who was getting GDNF or a control treatment. The procedure used to pump the GDNF into the brain was slightly different to that used in the Bristol study, and some have suggested that this may have contributed to the outcome of this study.

On 1st July 2004, Amgen announced that its clinical trial testing the efficacy of GDNF in treating advanced Parkinson’s had failed to demonstrate any clinical improvement after six months of use. Later that year (in September), Amgen halted the study completely citing two reasons:

  • Pre-clinical data from non-human primates that had been treated in the highest dosage group for six months (followed by a three-month washout period) indicated a significant loss of neurons in an area of the brain called the cerebellum (which is involved in coordinating movement)
  • They had detected “neutralizing antibodies” in two of the study participants.

The former was strange as it had never been detected in any other animal models previously reported, but the detection of antibodies was a more serious issue. Antibodies are made by cells to defend the body against foreign material. If the body begins to produce antibodies against GDNF, the immune system would clear the body of the GDNF drug, but also the body’s own natural supply of GDNF. The consequences of this are unknown, so Amgen decided to pull the plug on the trial.

What followed was a ugly chapter in the story of GDNF. Amgen refused to allow their study participants to continue to use GDNF when they requested it on compassion reasons. Lawyers then got involved (two lawsuits in 2005), but the judges decided in favour of Amgen.

There are many researchers around the world who still believe that GDNF represents an important treatment for Parkinson’s disease, and this has given rise to further clinical trials.

What is happening at the moment?

Currently there are several GDNF-based clinical trials being conducted. These trials have focused on three methods of delivery into the brain (specifically the striatum, which is the area of the brain where the most dopamine is released):

  1. Gene Therapy (GT)
  2. Encapsulated genetically modified cells (ECB)
  3. Pump delivery

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A section of human brain demonstrating the different methods

for the delivery of GDNF to the striatum. Source: EPFL

The gene therapy (GT) trials have used genetically modified viruses to deliver the GDNF family members. One of the main GT trials involved a virus that was modified so that it produced large amounts of neurturin. Subjects were injected in the brain (specifically the striatum) and then the study participants were followed for 15 months. Unfortunately, this study failed to demonstrate any meaningful improvement in subjects with Parkinson’s disease.

The Encapsulated genetically modified cells (ECB) approach for the delivery of GDNF has been developed by company called NSgene and the trial currently on-going and we are waiting to hear the results of this study.

And finally, a new pump clinical trial for GDNF trial being run in Bristol (UK). The trial is being run by a company called MedGenesis (and funded by ParkinsonsUK and the CurePDTrust). The research team in Bristol have recruited 36 people with Parkinson’s disease to take part in their 9-month trial.

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Dr Stephen Gill – Professor in Neurosurgery at University of Bristol – who conducting the current GDNF-pump study

This new trial should definitively tell us if there is a future for GDNF in Parkinson’s disease.  The results of the study are expected at the end of 2016.

Reasons why GDNF may not work

While we do not want to dampen any optimism regarding GDNF, we believe that it is important to supply all points of view and as much information as possible. That said, in 2012, researchers in Sweden discovered that the GDNF neuroprotective effect is blocked in cells over-expressing alpha-synuclein – the protein that clumps together in Parkinson’s disease. In agreement with this, they found that RET was also reduced in dopamine neurons in people with Parkinson’s disease. Thus, it may be that people with Parkinson’s disease have a reduced ability to respond to GDNF.

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Title: α-Synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons.
Authors: Decressac M, Kadkhodaei B, Mattsson B, Laguna A, Perlmann T, Björklund A.
Journal: Sci Transl Med. 2012 Dec 5;4(163):163ra156.
PMID: 23220632

Luckily, the Swedish researchers also found that another protein, called Nurr1, could rescue this reduction in GDNF response. And there is now a lot of research being conducted to investigate the positive effects of GDNF and Nurr1 in combination.

We will continue to follow this area and report any new findings as they come to hand.