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 ========================================================================== 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

========================================================================== Story Source: Materials provided by University_College_London. Note:
Content may be edited for style and length.


========================================================================== 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/05/230524181908.htm

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