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Time for a ‘brain dump’
October 2017
by Jeffrey Bouley  |  Email the author
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With our show preview of the annual meeting of the Society for Neuroscience this issue, it seemed appropriate to spend a little extra time here in the Research and Development section to do a roundup of several recent neurology-related stories that have come through the inbox, starting with Milan, Italy-based Axxam S.p.A, which in early September announced the start of a research collaboration with Sanofi designed to further optimize a number of lead series of small molecules targeted against a range of diseases of the central nervous system (CNS).
 
The program, initiated at Axxam via a high-throughput screen of the Axxam small-molecule screening library, yielded a number of tractable hit series. Subsequent multi-parameter optimization identified potent and selective molecules with high CNS exposures and showed promising results in disease-relevant pharmacology models.
 
Following an initial evaluation phase in-house, Sanofi and Axxam will continue the program under a joint research agreement with activities to be carried out at Axxam and Sanofi research facilities. If successful, Sanofi has an option to enter into a subsequent licensing agreement based on the research. The exact pharmacological target and financial terms of this agreement with Sanofi were not disclosed.
 
“We are excited to open this latest chapter of our interactions with Sanofi,” said Dr. Russell Thomas, director of discovery research at Axxam. “During the initial evaluation of our compounds in their laboratories we were impressed by the deep understanding of the target and its potential in addressing a broad range of neurodegenerative disorders with significant unmet medical needs. In addition, we have been extremely pleased by the collaborative spirit at Sanofi and look forward to working together to advance this initiative.”
 
In recent years, Axxam has received invaluable financial and scientific support from the Alzheimer’s Drug Discovery Foundation (ADDF).
 
A biomarker for Parkinson’s?
 
Parkinson’s disease is an insidious condition, given that by the time the typical motor dysfunctions like tremors or muscle rigidity have shown up, not only will parts of the brain have been irreversibly destroyed but also, the disease has probably already been in place for decades. In search of a way to identify the disease earlier, researchers led by Prof. Paul Wilmes, head of the Eco-Systems Biology Group at the Luxembourg Centre for Systems Biomedicine of the University of Luxembourg, may now have found one in the gut.
 
Specifically, they have shown that the bacterial community in the gut of Parkinson’s patients differs from that of healthy people even at a very early stage of the disease—the results of their work appeared recently in the scientific journal Movement Disorders.
 
The idea that Parkinson’s disease originates far outside the brain is not new; according to the “dual hit” hypothesis, a hitherto unknown pathogen intrudes into the body through two ports of entry: the nose or the gastrointestinal tract. Once there, it sets a pathological process in motion, above all the misfolding of the protein alpha-synuclein. The misfolding of this protein could propagate through the nerve pathways, where—decades later—it produces the typical clumping in the dopaminergic cells, known as Lewy bodies, that are characteristic of Parkinson’s.
 
The researchers led by Wilmes, together with physicians Prof. Brit Mollenhauer and Prof. Wolfgang Oertel and their teams in Göttingen, Kassel and Marburg, explored the question of whether the early events in the course of the disease also change the bacterial community (the microbiome) at the two possible ports of entry. They took samples from the nose and gut of 76 Parkinson’s patients and 78 healthy control people who are taking part in a long-term study. They also examined the microbiome of 21 subjects diagnosed with iRBD, or idiopathic rapid-eye-movement sleep behavior disorder (a group known to have a greatly elevated risk of developing Parkinson’s disease later in life). The bacterial community of the gut indeed differed considerably between all three groups.
 
“Parkinson’s patients could be differentiated from healthy controls by their respective gut bacteria,” said the first author Dr. Anna Heintz-Buschart from the Eco-Systems Biology Group. And the majority of the differential bacteria showed similar trends in the iRBD group. For example, certain germs were more prevalent in one group while the count was lower in others. In the samples from the subjects’ nasal cavities, however, the researchers found no such differences. The study also revealed that certain gut microbes are associated with non-motor Parkinson’s symptoms—for example, depression.
 
“We hope that, by comparing the groups, we will learn to better understand the role of the microbiome in the process of the disease and to find out what changes occur and when,” Wilmes explained. “This might deliver new starting points for early treatment of the disease. It would also be essential knowledge for one day being able to use the absence or presence of certain bacteria as a biomarker for early detection of the disease.”
 
Caprion collaborates with FNIH on Alzheimer’s biomarkers
 
Caprion Biosciences recently announced that it had entered a collaboration with the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium to measure protein biomarkers linked to early disease progression in Alzheimer’s. Under the collaboration, Caprion will use its ProteoCarta mass spec platform to measure the levels of five proteins in the cerebrospinal fluid of more than 200 subjects including patients with Alzheimer’s disease, mild cognitive impairment and healthy controls, with the goal of determining the ability of these proteins to track disease progression. The company will also measure an additional 140 CSF proteins that have been linked to Alzheimer’s and other central nervous system diseases.
 
“This partnership with the FNIH is a great example of Caprion’s ongoing commitment to identifying and validating biomarkers of CNS diseases,” Martin LeBlanc, Caprion’s CEO, said in a statement. “Our CNS ProteoCarta biomarker panel builds on Caprion’s expertise in large targeted protein assays in multiple therapeutic areas including Alzheimer’s, Parkinson’s and Huntington’s diseases.”
 
Developing a living model of the BBB
 
Nortis was recently awarded a $688,000 National Institutes of Health grant. The award will provide funding for the third year of a Small Business Innovation Research fast-track grant under award number R44NS095585 from the National Institute of Neurological Disorders and Stroke. 
 
The grant will allow Nortis to expand applications for its proprietary ParVivo system into the field of the human blood-brain barrier (BBB), addressing the critically unmet need for more effective in-vitro testing systems that model human brain diseases such as Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, stroke and cancer.
 
“Understanding how drugs are transported across the blood-brain barrier and interact with the brain presents a significant scientific challenge,” said Dr. Thomas Neumann, CEO of Nortis and principal investigator on this project. ”More predictive preclinical models based on human tissue are urgently needed to reduce costs and minimize clinical trial failures. This grant will help us develop new in-vitro alternatives to traditional pharmaceutical drug development testing on laboratory animals.”
 
Code: E101710

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