New chemical compound shows potential in nerve regeneration

The study, published in Nature, have identified a chemical compound, named “1938”, which activates the PI3K signaling pathway and is involved in cell growth. The results of this early research showed that the compound increased the growth of neurons in nerve cells and, in animal models, reduced damage to heart tissue after major trauma and regenerated lost motor function in a model of nerve injury.

Although further research is needed to translate these findings into the clinic, 1938 is one of the few compounds in development that can promote nerve regeneration, for which there are currently no approved drugs.

Phosphoinositide 3-kinase (PI3K) is a type of enzyme that helps control cell growth. It is active in various situations, such as the initiation of wound healing, but its functions can also be hijacked by cancer cells to allow them to proliferate. As a result, anticancer drugs have been developed that inhibit PI3K to limit tumor growth. But the clinical potential of PI3K pathway activation remains underexplored.

Dr Roger Williams, lead author of the study from the MRC Molecular Biology Laboratory, said: “Kinases are ‘molecular machines’ that are essential for controlling the activities of our cells, and they are targets for a wide range of range of drugs. Our goal was to find activators of one of these molecular machines, with the aim of improving the functioning of the machine. We found that we could directly activate a kinase with a small molecule to achieve therapeutic benefits by protecting the heart from injury and stimulating neuronal regeneration in animals. studies.”

In this study, researchers from UCL and MRC LMB worked with researchers from AstraZeneca to screen thousands of molecules from its library of chemical compounds to create one that could activate the PI3K signaling pathway. They found that the compound named 1938 was able to reliably activate PI3K and its biological effect was assessed by experiments on heart tissue and nerve cells.

Researchers at UCL’s Hatter Cardiovascular Institute found that administering 1938 during the first 15 minutes of blood flow restoration after a heart attack provided substantial tissue protection in a preclinical model. Usually areas of dead tissue form when blood flow is restored, which can lead to heart problems later in life.

When 1938 was added to laboratory-grown nerve cells, neuron growth was dramatically increased. A rat model with sciatic nerve injury was also tested, with 1938 delivery to the injured nerve resulting in increased recovery in the hind paw muscle, indicating nerve regeneration.

Professor James Phillips (UCL School of Pharmacy), lead author of the study, said: “There are currently no approved drugs to regenerate nerves, which can be damaged as a result of injury or trauma. disease, so there is a huge unmet need. Our results show that there is potential for drugs that activate PI3K to accelerate nerve regeneration and, importantly, localized delivery methods could avoid the problems of off-target effects that have seen other compounds fail.

Given the positive results, the group is now working to develop new therapies for peripheral nerve injuries, such as those sustained in severe hand and arm injuries. They are also investigating whether PI3K activators could be used to help treat central nervous system damage, for example due to spinal cord injury, stroke or neurodegenerative disease.

Professor Bart Vanhaesebroeck (UCL Cancer Institute), lead author of the study, said: “This is an excellent example of interdisciplinary research, in which people with expertise ranging from basic science, to the development of drugs and clinical studies join forces around an innovative idea, while crossing the boundaries between academia and industry. It is difficult to obtain funding for blue sky research of this type in a world of increasing specialization, but I hope that this project can provide a model for future ambitious research. »

An important factor in the overall success of the study was the UCL Office of Translational Research’s drug discovery group supporting the drug discovery program and participation in AstraZeneca’s Open Innovation program, which sees the company collaborate with academics who have innovative ideas to advance drug discovery. and development.

Mike Snowden, Senior Vice President, Discovery Sciences at AstraZeneca, said, “Our Open Innovation program aims to create an open research environment that connects our expertise and technologies with innovative and ambitious research ideas from collaborators like UCL and MRC LMB, with the aim of discovering new biology and biological mechanisms.”

This research was funded by Wellcome, UKRI, MRC, NIHR UCLH Biomedical Research Center, European Union Horizon 2020, British Heart Foundation, Rosetrees Trust and CRUK.