The Operating Theatre Journal - Journal - Page 8
New chemical compound demonstrates potential in
nerve regeneration
Developing new therapies
Research has identified a new compound
that can stimulate nerve regeneration after
injury and protect cardiac tissue from the
sort of damage seen in heart attack.
The research is led by UCL, in partnership
with the Medical Research Council (MRC)
Laboratory of Molecular Biology (LMB) and
AstraZeneca.
The study, published in Nature, identified
a chemical compound, named ‘1938’, that
activates the phosphoinositide 3-kinase (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
• reduced heart tissue damage after major
trauma
• 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.
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.
Screening thousands of
molecules
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.
‘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.
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.
Innovative ideas
What is PI3K?
PI3K is a type of enzyme that helps to control
cell growth.
Increased neuron growth
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.
Molecular machines
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.
8
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.
Ordinarily, areas of dead tissue form when
blood flow is restored that can lead to heart
problems later in life.
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.
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.
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.
THE OPERATING THEATRE JOURNAL
An important factor in the overall success of
the study was participation in AstraZeneca’s
‘Open Innovation’ programme.
The programme 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:
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Wellcome
UK Research and Innovation
MRC
National Institute for Health and Care
Research University College London
Hospitals Biomedical Research Centre
EU Horizon 2020
British Heart Foundation
Rosetrees Trust
Cancer Research UK
Source: UKRI
www.otjonline.com