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New drug may treat and limit progression of Parkinson's disease

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Lynn Rotanno
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« on: October 11, 2017, 01:58:39 pm »


Science News

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New drug may treat and limit progression of Parkinson's disease

Multifunctional compound D-512 provides longer relief than current medications
Date:July 31, 2017 Source:Binghamton University Summary:Researchers have developed a new drug that may limit the progression of Parkinson's disease while providing better symptom relief to potentially hundreds of thousands of people with the disease. Share:

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Researchers at Binghamton University have developed a new drug that may limit the progression of Parkinson's disease while providing better symptom relief to potentially hundreds of thousands of people with the disease.







Symptoms of Parkinson's disease are commonly managed using a selective dopamine receptor agonists. While these drugs are useful in early-stage Parkinson's, they tend to lose efficacy in later disease stages. As important, currently marketed drugs do not appear to modify disease progression. A research team including Binghamton University psychology professor Chris Bishop and former graduate student David Lindenbach recently employed a preclinical model of Parkinson's disease to compare the effects of the dopamine agonist ropinirole to their new drug, known as D-512. Results demonstrated that D-512 was more efficacious than ropinirole in treating the symptoms of Parkinson's disease while also prolonging the time window in which the animals showed benefits. These findings followed on the heels of prior work by this collaborative group which demonstrated that D-512 may also protect again the progression of Parkinson's disease.

"A major issue for Parkinson's disease patients is the need to take multiple medications, multiple times per day. So we were quite astounded to discover that our new compound, D-512, was superior to the widely-used drug, ropinirole, in terms of maximal symptom relief and duration of action," said Lidenbach.

The researchers also noted that D-512 may have fewer side effects than current medications. When patients take anti-parkinsonian drugs, over time they develop hyperkinetic movements that are hard to control, called dyskinesia. Coupled with D-512's beneficial effects on motor symptoms, they argue that it therapeutic features are highly desirable.






"What you have is a better therapeutic index with our drug versus the current medication. And when you couple that with the fact that it's seemingly multifunctional...then what we have is a compound that just isn't currently available to Parkinson's patients but that we think has a lot of promise," said Bishop.

"D-512 is unique because it not only treats the symptoms of Parkinson's disease, but the molecule itself is an antioxidant," said Lindenbach. "This antioxidant property is important because a major cause of Parkinson's disease appears to be excessive oxidative stress is a small group of movement-facilitating brain cells."

The researchers are currently at a pre-clinical phase. Their goals are two-fold: to understand how D-512 actually provides neural protection and therapeutic relief, while also looking at different models of Parkinson's disease that will translate into the clinic.

"There are some intermediate steps that we may be involved in. I think one of these is determining whether this compound works in later stages to slow down the disease progression. It seems to work very well if you give it really early, before the disease takes hold -- but looking at it at later time points and determining whether it can slow the disease down once it's really taken hold, also has important implications," said Bishop.








Story Source:

Materials provided by Binghamton University. Note: Content may be edited for style and length.
 


Journal Reference:
1.David Lindenbach, Banibrata Das, Melissa M Conti, Samantha M Meadows, Aloke K Dutta, Christopher Bishop. D-512, a novel dopamine D2 / D3 receptor agonist, demonstrates superior anti-parkinsonian efficacy over ropinirole in parkinsonian rats. British Journal of Pharmacology, 2017; DOI: 10.1111/bph.13937

 


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Binghamton University. "New drug may treat and limit progression of Parkinson's disease: Multifunctional compound D-512 provides longer relief than current medications." ScienceDaily. ScienceDaily, 31 July 2017. <www.sciencedaily.com/releases/2017/07/170731164018.htm>.






 

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Lynn Rotanno
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« Reply #1 on: October 11, 2017, 02:00:13 pm »


What's Hot in PD? What Led Scientists to Believe a Cancer Drug Could Treat Parkinson’s?
 


http://www.parkinson.org/find-help/blogs/what-s-hot




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The recent media blitz about a leukemia drug named Nilotinib as a potential treatment for Parkinson’s disease resulted in thousands of patients and family members phoning their doctors and our 1-800-4PD-INFO Helpline requesting access to this drug. The National Parkinson Foundation quickly responded with a public statement recommending that patients not pursue this therapy unless under a clinical trial. There were serious concerns in the size and methodology of this initial report which was recently presented at the Society for Neuroscience meeting. Patients and families should be aware that the results have yet to be published in a peer-reviewed paper. Please see the statement NPF Recommends Further Study but Not Clinical Use of this Investigational Drug. In this month’s What’s Hot in PD? column I will address the question as to what actually led scientists to believe a cancer drug could treat Parkinson’s disease?

Approximately 10% of Parkinson’s disease cases have been associated with gene defects. These changes in the DNA have allowed researchers to hone in on the mechanisms that may be responsible for this devastating disease. Scientists around the world have become adept at preparing animal models of Parkinson’s disease by using the observed changes in the DNA occurring in some human cases. Ted and Valina Dawson, a husband and wife team located at the National Parkinson Foundation Center of Excellence at Johns Hopkins University recently published an important paper on how the most common genetic subtype of Parkinson’s disease (LRRK2) leads to degeneration and to cell death.

Mutations in the DNA of Parkinson’s disease patients located in the leucine-rich repeat kinase 2 region (LRRK2) represent the most common genetic cause of Parkinson's disease. Because LRRK2 is the most common gene defect responsible for Parkinson’s disease, it has been a focus of many laboratories. So what does LRRK2 do? One of the jobs of LRRK2 in the brain seems to be to tag proteins. When proteins are tagged, this signals the brain to change its cell manufacturing process. However, when bad LRRK2 tags proteins, it results in over-manufacturing. An excess of proteins can lead to the death of brain cells. Bad LRRK2 performs its tagging function by attaching phosphate groups. Bad LRRK2 leads to increases in proteins through its action on a part of the cell called ribosomal s15. The Dawson duo demonstrated that by removing the phosphate group that tags s15 actually prevented degeneration. Further, by administering a low dose of anisomycin, which blocks protein production, the Dawson strategy also rescued flies with LRRK2 mutations.

Though these findings are exciting, we should remember that they have yet to be translated into humans. The Dawsons have suggested that one way to treat LRRK2 Parkinson’s disease would be to simply block phosphorylation of the s15 ribosomal protein. This idea may be formulated into a strategy for a future human clinical drug trial. Further, if there is a clinical trial, we will need a way to measure success and to monitor s15 phosphorylation. Phosphorylation could possibly be a blood or other biomarker of bad LRRK2 activity. The Dawsons have also for many years been investigating a class of drugs called the C-Abl tyrosine kinase inhibitors because of findings in another genetic form of Parkinson’s disease called PARKIN. The PARKIN protein is modified by c-Abl and this interaction could be the critical step leading to accumulation of toxic proteins in the brain. C-Abl inhibitors have been proposed as a way to block this protein buildup. The C-Abl pathway is where Nilotinib is thought to act, and this was proposed several years ago as a potential treatment for the protein buildups in Parkinson’s disease.

The Hopkins team carefully examined Nilotinib in 2013 (see http://www.ncbi.nlm.nih.gov/pubmed/24786396). “Our findings… suggest that Nilotinib and other brain penetrant c-Abl inhibitors could be used as disease modifying therapies in Parkinson’s disease. Consistent with this notion is the observation that Nilotinib reverses the loss of dopamine neurons and improves motor behavior in α-synuclein PD models. Based on the findings reported here and elsewhere, future studies are needed to identify the optimal dosing and administration to take advantage of the full neuroprotective potential of Nilotinib. Alternatively other c-Abl inhibitors with better pharmacokinetic properties and safety profiles may need to be identified to take advantage of inhibition of c-Abl as a disease modifying therapy for PD.”

Though the first dozen or so patients tested at the Georgetown site had positive effects, there were serious limitations to this study that patients and family members should be aware of:
•A very small number of patients (about a dozen); these trials usually require hundreds of patients to demonstrate an effect
•The design really only supported safety, but not effectiveness or efficacy
•The doses of the cancer drug administered were low, and if higher doses are required in future studies, toxicity may possibly limit this approach
•Many of the motor and cognitive outcomes improved in this small study and if a controlled study were performed it would be unlikely for all of these outcomes to improve
•Videotapes are not the most optimal way to assess outcome in a small study, and videotape methodology when not applied in a blinded and standardized fashion can lead to a large placebo effect or to an error in outcome interpretation
•There was no blinded comparison to a placebo or to another therapeutic approach

The good news, however, is that since 2013 Dawson and other investigators have been investigating potentially safer and more effective c-Abl inhibitor drug options. Patients and families should feel reassured that the scientific discoveries that led Parkinson’s scientists to repurpose Nilotinib, may also lead them to other and potentially better c-Abl strategies.

References

Okun, MS. 10 Breakthrough Therapies for Parkinson's Disease. Books4Patients. 2015.

You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Health Center for Movement Disorders and Neurorestoration. Dr. Okun is also the author of the Amazon #1 Parkinson's Best Seller 10 Secrets to a Happier Life and 10 Breakthrough Therapies for Parkinson's Disease.
.




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Lisa Wolfe
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« Reply #2 on: October 11, 2017, 10:31:37 pm »

New hope for a Parkinson's disease cure as scientists find brain cells can be reprogrammed to replicate those lost

    A selection of small molecules can make brain cells produce the chemical messenger dopamine, which is lost in Parkinson's sufferers, causing tremors
    When the therapy was given to mice, their Parkinson-like symptoms improved 
    The treatment may overtake cell transplants, which were previously thought to be the only hope of a cure and require immune system-suppressing drugs

By Alexandra Thompson Health Reporter For Mailonline

Published: 11:02 EDT, 13 April 2017 | Updated: 11:40 EDT, 13 April 2017

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Parkinson's disease affects around 127,000 people in the UK.

As the condition has no cure, sufferers are forced to endure the debilitating movement disorder.

Yet, scientists may be one step closer to finding a solution.

Researchers used a selection of small molecules to reprogramme brain cells so that they produced the chemical messenger dopamine, which regulates movement.

In Parkinson sufferers, dopamine-producing brain cells have died, causing tremors and moving difficulties. 
Parkinson Disease occurs as the cells that produce the chemical messenger dopamine have died, causing tremors. The new treatment may reprogramme brain cells to make dopamine
+1

Parkinson Disease occurs as the cells that produce the chemical messenger dopamine have died, causing tremors. The new treatment may reprogramme brain cells to make dopamine
WHAT IS PARKINSON'S DISEASE?

Parkinson's disease is a progressive neurological disease.

It develops gradually, sometimes starting with a barely noticeable tremor in just one hand.

Other symptoms include slowed movement and rigid muscles.

Scientist suspect a mix of genetic and environmental factors are responsible.

It has no cure with treatment focusing on controlling symptoms. 

Source: NHS Choices and Parkinson's UK

Swedish scientists tested a cocktail of molecules in mice with Parkinson-like symptoms.

After treatment, the mice's symptoms appeared to improve.

The revolutionary approach may overtake brain cell transplants, which was previously thought to be the only hope of a cure.

According to study author Dr Ernest Arenas, this new treatment will not require the immune system-suppressing drugs needed in transplants.

The therapy makes dopamine-producing cells from those already in the brain, meaning patients will not reject them, which is a risk with transplants, he said.

Although the potential cure could transform Parkinson's treatment, scientists warn further animal studies are needed before the approach can be tried in humans.

Professor David Dexter, deputy director, Parkinson's UK said: 'Further development of this technique is now needed,' the BBC reported.

'If successful, it would turn this approach into a viable therapy that could improve the lives of people with Parkinson's and, ultimately, lead to the cure that millions are waiting for.' 

This comes after scientists from the University of Oxford found infection with hepatitis B and C viruses raises the risk of Parkinson's by up to 76 per cent.

This is thought to be due to the viruses targeting the motor system once they leave the liver.



http://www.dailymail.co.uk/health/article-4405122/Scientists-closer-finding-Parkinson-s-cure.html
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Lisa Wolfe
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« Reply #3 on: October 11, 2017, 10:37:13 pm »

s Refresh Biotech map
Scottish Scientists Could Hold the Key to Unlocking Parkinson’s Disease
From The Bench
Alex Dale Alex Dale on 11/10/2017

A decade of work has culminated in researchers reconstructing a protein that is key to defending the brain against Parkinson’s disease.

Researchers at the University of Dundee have made a breakthrough by uncovering the 3D structure of an enzyme, PINK1, that can protect the brain against Parkinson’s disease. The disease is characterised by the degeneration of neurons, mainly in the motor system, causing symptoms such as tremors and difficulty walking. By knowing more about the protein, researchers now believe that they are in a far better position to therapeutically exploit its protective qualities.

Mutations in the gene encoding PINK1 have been identified in patients with early-onset Parkinson’s, which alerted researchers to it as a potential therapeutic target. PINK1 encodes a kinase enzyme that plays an important role in protecting brain cells against stress. Patients with mutated forms of the protein lose its protective effect is lost, leading to the degeneration of cells controlling movement that account for Parkinson’s symptoms.

Functional PINK1 deals with damaged mitochondria, targeting them for degradation with the help of two proteins, ubiquitin and parkin, which form part of the ubiquitin-proteasome system that degrades faulty proteins. The Scottish study has shed light on how PINK1 manages this, by spotting unique control elements that recruit ubiquitin and parkin. This explains why mutation of the enzyme can have such a devastating effect.

Changes to neurons during Parkinson’s disease. Reduced release of dopamine gives rise to common symptoms of the conditions, including tremors.

Dr Miratul Muqit, Wellcome Trust Senior Clinical Fellow and Consultant Neurologist explained the implications these findings could have on Parkinson’s therapies: “Solving the structure and workings of PINK1 gives us crucial insights into how it exerts a protective role in Parkinson’s… That knowledge can lead to the development of new drugs which could be designed to ‘switch on’ PINK1 to the benefit of patients with Parkinson’s.”

Regulatory bodies appear to be particularly tough when it comes to getting a drug targeting the CNS onto the market. But, Newron, one of our top 4 biotechs in Milan, managed it earlier this year with Xadago, which received approval to treat Parkinson’s. Swiss biotech, Prexton Therapeutics, has launched a Phase II trial to test whether its candidate can ease the motor symptoms of the condition.

The research represents a breakthrough in the molecular understanding of Parkinson’s disease, which had been lacking new approaches to treatment until Xadago entered the market earlier this year. The challenge now is to find a way to successfully target the protein therapeutically, perhaps, for example, in the form of gene therapy.

Images – Lightspring, Artwork studio BKK / shutterstock.com

https://labiotech.eu/scottish-scientists-hold-key-unlocking-parkinsons-disease/
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If nothing we do matters, then all that matters is what we do. The smallest act of kindness can be the greatest thing in the world.
Lisa Wolfe
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« Reply #4 on: October 11, 2017, 10:37:49 pm »

s Refresh Biotech map
Scottish Scientists Could Hold the Key to Unlocking Parkinsonís Disease
From The Bench
Alex Dale Alex Dale on 11/10/2017

A decade of work has culminated in researchers reconstructing a protein that is key to defending the brain against Parkinsonís disease.

Researchers at the University of Dundee have made a breakthrough by uncovering the 3D structure of an enzyme, PINK1, that can protect the brain against Parkinsonís disease. The disease is characterised by the degeneration of neurons, mainly in the motor system, causing symptoms such as tremors and difficulty walking. By knowing more about the protein, researchers now believe that they are in a far better position to therapeutically exploit its protective qualities.

Mutations in the gene encoding PINK1 have been identified in patients with early-onset Parkinsonís, which alerted researchers to it as a potential therapeutic target. PINK1 encodes a kinase enzyme that plays an important role in protecting brain cells against stress. Patients with mutated forms of the protein lose its protective effect is lost, leading to the degeneration of cells controlling movement that account for Parkinsonís symptoms.

Functional PINK1 deals with damaged mitochondria, targeting them for degradation with the help of two proteins, ubiquitin and parkin, which form part of the ubiquitin-proteasome system that degrades faulty proteins. The Scottish study has shed light on how PINK1 manages this, by spotting unique control elements that recruit ubiquitin and parkin. This explains why mutation of the enzyme can have such a devastating effect.

Changes to neurons during Parkinsonís disease. Reduced release of dopamine gives rise to common symptoms of the conditions, including tremors.

Dr Miratul Muqit, Wellcome Trust Senior Clinical Fellow and Consultant Neurologist explained the implications these findings could have on Parkinsonís therapies: ďSolving the structure and workings of PINK1 gives us crucial insights into how it exerts a protective role in ParkinsonísÖ That knowledge can lead to the development of new drugs which could be designed to Ďswitch oní PINK1 to the benefit of patients with Parkinsonís.Ē

Regulatory bodies appear to be particularly tough when it comes to getting a drug targeting the CNS onto the market. But, Newron, one of our top 4 biotechs in Milan, managed it earlier this year with Xadago, which received approval to treat Parkinsonís. Swiss biotech, Prexton Therapeutics, has launched a Phase II trial to test whether its candidate can ease the motor symptoms of the condition.

The research represents a breakthrough in the molecular understanding of Parkinsonís disease, which had been lacking new approaches to treatment until Xadago entered the market earlier this year. The challenge now is to find a way to successfully target the protein therapeutically, perhaps, for example, in the form of gene therapy.

Images Ė Lightspring, Artwork studio BKK / shutterstock.com

https://labiotech.eu/scottish-scientists-hold-key-unlocking-parkinsons-disease/
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Lisa Wolfe
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Posts: 4682



« Reply #5 on: October 11, 2017, 10:39:09 pm »

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