MSGID: 1:317/3 646ee4c2   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    New chemical compound demonstrates potential in nerve regeneration   
      
      
     Date:   
         May 24, 2023   
     Source:   
         University College London   
     Summary:   
         Recent research has identified a new compound that can stimulate   
         nerve regeneration after injury, as well as protect cardiac tissue   
         from the sort of damage seen in heart attack.   
      
      
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   FULL STORY   
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   Research led by UCL, in partnership with the MRC Laboratory of Molecular   
   Biology (MRC LMB) and AstraZeneca, has identified a new compound that   
   can stimulate nerve regeneration after injury, as well as protect cardiac   
   tissue from the sort of damage seen in heart attack.   
      
   The study, published in Nature, identified a chemical compound, named   
   '1938', that activates the PI3K signalling pathway, and is involved in   
   cell growth.   
      
   Results from this early research showed the compound increased neuron   
   growth in nerve cells, and in animal models, it reduced heart tissue   
   damage after major trauma and regenerated lost motor function in a model   
   of nerve injury.   
      
   Though further research is needed to translate these findings into the   
   clinic, 1938 is one of just a few compounds in development that can   
   promote nerve regeneration, for which there are currently no approved   
   medicines.   
      
   Phosphoinositide 3-kinase (PI3K) is a type of enzyme that helps to control   
   cell growth. It is active in various situations, such as initiating wound   
   healing, but its functions can also be hijacked by cancer cells to allow   
   them to proliferate. As a result, cancer drugs have been developed that   
   inhibit PI3K to restrict tumour growth. But the clinical potential of   
   activating the PI3K pathway remains underexplored.   
      
   Dr Roger Williams, a senior author of the study from the MRC Laboratory   
   of Molecular Biology, said: "Kinases are 'molecular machines' that are   
   key to controlling the activities of our cells, and they are targets   
   for a wide range of drugs. Our aim was to find activators of one of   
   these molecular machines, with the goal of making the machine work   
   better. We found that we can directly activate a kinase with a small   
   molecule to achieve therapeutic benefits in protecting hearts from injury   
   and stimulating neural regeneration in animal studies."  In this study,   
   researchers from UCL and MRC LMB worked with researchers from AstraZeneca   
   to screen thousands of molecules from its chemical compound library to   
   create one that could activate the PI3K signalling pathway. They found   
   that the compound named 1938 was able to activate PI3K reliably and its   
   biological effect were assessed through experiments on cardiac tissue   
   and nerve cells.   
      
   Researchers at UCL's Hatter Cardiovascular Institute found that   
   administering 1938 during the first 15 minutes of blood flow restoration   
   following a heart attack provided substantial tissue protection in a   
   preclinical model.   
      
   Ordinarily, areas of dead tissue form when blood flow is restored that   
   can lead to heart problems later in life.   
      
   When 1938 was added to lab-grown nerve cells, neuron growth was   
   significantly increased. A rat model with a sciatic nerve injury was also   
   tested, with delivery of 1938 to the injured nerve resulting in increased   
   recovery in the hind leg muscle, indicative of nerve regeneration.   
      
   Professor James Phillips (UCL School of Pharmacy), a senior author of   
   the study, said: "There are currently no approved medicines to regenerate   
   nerves, which can be damaged as a result of injury or disease, so there's   
   a huge unmet need. Our results show that there's potential for drugs   
   that activate PI3K to accelerate nerve regeneration and, crucially,   
   localised delivery methods could avoid issues with off-target effects   
   that have seen other compounds fail."  Given the positive findings,   
   the group is now working to develop new therapies for peripheral nerve   
   damage, such as those sustained in serious hand and arm injuries. They   
   are also exploring whether PI3K activators could be used to help treat   
   damage in the central nervous system, for example due to spinal cord   
   injury, stroke or neurodegenerative disease.   
      
   Professor Bart Vanhaesebroeck (UCL Cancer Institute), a senior author   
   of the study, said: "This is a prime example of interdisciplinary   
   research, in which people with expertise ranging from basic science, drug   
   development and clinical studies join forces around an innovative idea,   
   whilst also crossing boundaries between academia and industry. 'Blue   
   sky' research of this kind is difficult to get funding for in a world   
   of increasing specialisation, but hopefully this project can provide   
   something of a model for future ambitious research."  An important factor   
   in the overall success of the study was UCL's Drug Discovery Group from   
   the Translational Research Office supporting the drug discovery programme   
   and participation in AstraZeneca's 'Open Innovation' programme, which   
   sees the company collaborating with academics that have innovative ideas   
   to advance drug discovery and development.   
      
   Mike Snowden, Senior Vice President, Discovery Sciences at AstraZeneca,   
   said: "Our Open Innovation programme aims to create an open research   
   environment that connects our expertise and technologies with the   
   innovative and ambitious research ideas of collaborators like UCL and MRC   
   LMB, with the aim of uncovering novel biology and biological mechanisms."   
   This research was funded by Wellcome, UKRI, MRC, NIHR UCLH Biomedical   
   Research Centre, European Union Horizon 2020, the British Heart   
   Foundation, the Rosetrees Trust and CRUK.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Neuropathy # Nervous_System # Disability # Heart_Disease   
             o Mind_&_Brain   
                   # Brain_Injury # Neuroscience # Depression # Alzheimer's   
       * RELATED_TERMS   
             o Artificial_heart o Heart_rate o Ischaemic_heart_disease   
             o Brain_damage o CPR o Defibrillation o Heart_failure o   
             Traumatic_brain_injury   
      
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   Story Source: Materials provided by University_College_London. Note:   
   Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Grace Q. Gong, Benoit Bilanges, Ben Allsop, Glenn R. Masson,   
      Victoria   
         Roberton, Trevor Askwith, Sally Oxenford, Ralitsa R. Madsen,   
         Sarah E.   
      
         Conduit, Dom Bellini, Martina Fitzek, Matt Collier, Osman Najam,   
         Zhenhe He, Ben Wahab, Stephen H. McLaughlin, A. W. Edith Chan,   
         Isabella Feierberg, Andrew Madin, Daniele Morelli, Amandeep Bhamra,   
         Vanesa Vinciauskaite, Karen E. Anderson, Silvia Surinova, Nikos   
         Pinotsis, Elena Lopez-Guadamillas, Matthew Wilcox, Alice Hooper,   
         Chandni Patel, Maria A.   
      
         Whitehead, Tom D. Bunney, Len R. Stephens, Phillip T. Hawkins,   
         Matilda Katan, Derek M. Yellon, Sean M. Davidson, David M. Smith,   
         James B.   
      
         Phillips, Richard Angell, Roger L. Williams, Bart Vanhaesebroeck. A   
         small-molecule PI3Ka activator for cardioprotection and   
         neuroregeneration. Nature, 2023; DOI: 10.1038/s41586-023-05972-2   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/05/230524181908.htm   
      
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