With your good chance of getting Parkinsons.
Parkinson’s Disease May Have Link to Stroke March 2017
Are your doctor and stroke hospital being responsible and doing any followup to get research going? OR is incompetence going to prevail?
Or will NOTHING BE DONE since everyone in stroke is waiting for SOMEONE ELSE TO SOLVE THE PROBLEM?
Tackling Parkinson’s With Targeted Drug Discovery
Tue, 02/12/2019 - 12:12pm
by Nick Moore, PhD, Principal Scientific Advisor at Charles River Laboratories
The
failures and lack of progress in the development of new treatments for
neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease,
are well documented. But, finally, for patients who are desperately
awaiting treatment, things may be changing. Advances in our
understanding of genetics have given clear direction for the potential
development of new treatments.
In the area of Parkinson’s disease, for example, mutations in the
gene encoding leucine-rich repeat kinase (LRRK2) have been identified
as one of the most common causes of familial Parkinson’s. A recent study
suggests LRRK2 activation may also be involved in the pathogenesis of
idiopathic Parkinson’s (Parkinson’s with no known genetic or
environmental cause). This evidence makes LRRK2 inhibition an attractive
target for novel drug development. If researchers can inhibit the
overactive enzyme, they may be able to prevent the downstream changes
that lead to the loss of dopamine in the brain, which ultimately causes
the motor and cognitive symptoms of Parkinson’s.
Developing novel agents for neurodegenerative diseases has always been a challenge, and discovering new treatments, for any disease area, is never simple. Drug discovery requires talented individuals from multiple disciplines to come together, working as a team with a common goal. In the past, some thought that increasing the scale of the process would translate into increased numbers of candidates coming out of the pipeline. However today, it is no longer a matter of ‘number of shots on goal’ but ‘getting the ball in the back of the net.’
By carefully understanding the underlying process involved in the disease, it is possible to target critical processes and develop selective compounds that modify the process, leading to a reduction in the progression of the disease. To be able to understand these changes, we must reach out to multiple partners and work together. Academics, non-profit foundations, industry, and contract research organizations can all play a part in combining their skills and knowledge to develop novel disease-modifying treatments. These days no one partner has all the knowledge and experience ‘to get the ball in the back of the net.’ It requires a significant team effort with multiple groups bringing together their individual specialized skills and expertise to solve the problem.
Investigating LRRK2
In collaboration with The Michael J. Fox Foundation for Parkinson’s Research, industry, and academics, Charles River worked across multiple sites to understand the role of LRRK2 in Parkinson’s, and its possible inhibition. Many compounds from different chemical classes have been synthesized and tested in cell-based assays to inhibit the activity of LRRK2. Cell-based models are a vital initial tool to test the efficacy of these compounds. Robust cell-based models can be used to rapidly screen the hundreds of compounds synthesized by the medicinal chemists.
Compounds with potency, selectivity, and drug-like properties can then be further validated in research models of Parkinson's. However, before any compound can go into the research models, researchers need to demonstrate target engagement and an acceptable side-effect profile, plus the right drug-like characteristics to be effective in Parkinson’s patients. These properties include characteristics like metabolic stability (you don’t want the compound to break down too rapidly). Compounds will also be assessed to confirm they do not interact with targets that may lead to either genotoxicity or cardiovascular risk. These cell-based assays, referred to as ‘off-target’ assays, allow the careful selection of only compounds likely to be successful in more advanced models and in people. Using these ‘off-target’ cell-based assays has drastically reduced the number of failures moving forward and importantly, reduced the numbers of research models needed in later stage studies.
Deeper Insights
Developing novel agents for neurodegenerative diseases has always been a challenge, and discovering new treatments, for any disease area, is never simple. Drug discovery requires talented individuals from multiple disciplines to come together, working as a team with a common goal. In the past, some thought that increasing the scale of the process would translate into increased numbers of candidates coming out of the pipeline. However today, it is no longer a matter of ‘number of shots on goal’ but ‘getting the ball in the back of the net.’
By carefully understanding the underlying process involved in the disease, it is possible to target critical processes and develop selective compounds that modify the process, leading to a reduction in the progression of the disease. To be able to understand these changes, we must reach out to multiple partners and work together. Academics, non-profit foundations, industry, and contract research organizations can all play a part in combining their skills and knowledge to develop novel disease-modifying treatments. These days no one partner has all the knowledge and experience ‘to get the ball in the back of the net.’ It requires a significant team effort with multiple groups bringing together their individual specialized skills and expertise to solve the problem.
Investigating LRRK2
In collaboration with The Michael J. Fox Foundation for Parkinson’s Research, industry, and academics, Charles River worked across multiple sites to understand the role of LRRK2 in Parkinson’s, and its possible inhibition. Many compounds from different chemical classes have been synthesized and tested in cell-based assays to inhibit the activity of LRRK2. Cell-based models are a vital initial tool to test the efficacy of these compounds. Robust cell-based models can be used to rapidly screen the hundreds of compounds synthesized by the medicinal chemists.
Compounds with potency, selectivity, and drug-like properties can then be further validated in research models of Parkinson's. However, before any compound can go into the research models, researchers need to demonstrate target engagement and an acceptable side-effect profile, plus the right drug-like characteristics to be effective in Parkinson’s patients. These properties include characteristics like metabolic stability (you don’t want the compound to break down too rapidly). Compounds will also be assessed to confirm they do not interact with targets that may lead to either genotoxicity or cardiovascular risk. These cell-based assays, referred to as ‘off-target’ assays, allow the careful selection of only compounds likely to be successful in more advanced models and in people. Using these ‘off-target’ cell-based assays has drastically reduced the number of failures moving forward and importantly, reduced the numbers of research models needed in later stage studies.
MRI measurements using BOLD activation mapping of an amphetamine-induced
signal change in the brain of the 6-OHDA rat model of Parkinson’s
disease. Credit: Charles River Laboratories
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