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New Compound May Promote Nerve Regeneration, Prevent Heart Damage

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A study has identified a new compound that can stimulate nerve regeneration after injury and protect against cardiac damage after heart attacks in laboratory and animal models. The research is published in Nature.

Tackling recovery after cell damage

During a heart attack, blood vessels supplying oxygen and nutrients to the heart become blocked, damaging cells and eventually leading to cell death. Nerve cells can also sustain damage after trauma that can lead to loss of function in the affected limbs.

Many cell types, such as neurons and heart muscle cells, have a limited ability to repair themselves. Therefore, it is vital to find ways to prevent damage from occurring after injury. There are no approved drugs to boost nerve regeneration as well as very few compounds currently in development.

In the current study, researchers from University College London (UCL) in collaboration with the Medical Research Council (MRC) Laboratory of Molecular Biology and AstraZeneca have identified a new compound – designated “1938” – which they demonstrate can reduce heart damage and regenerate lost motor function after injury in animal models.

Encouraging data from animal models

The researchers found that 1938 activates a vital cellular growth mechanism called the phosphoinositide 3-kinase (PI3K) pathway. PI3K is typically activated during wound healing, though the process is also frequently hijacked by cancer cells to increase their growth. This pathway has therefore become a valuable target for the development of anti-cancer inhibitor drugs.

However, the clinical potential of drugs that activate the PI3K pathway remains underexplored. The new research collaboration used a library of thousands of chemical compounds to find candidates that could activate PI3K signaling, ultimately identifying 1938 as a reliable activator.

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“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, localized delivery methods could avoid issues with off-target effects that have seen other compounds fail,” said Prof. James Phillips, co-senior author of the study and professor of regenerative medicine in the UCL School of Pharmacy.

Experiments to measure the effect of 1938 on cardiac tissue and nerve cells soon followed. They found that administering 1938 during the first 15 minutes of blood flow restoration after a heart attack in a preclinical model provided significant protection against damage.

Furthermore, neuron growth significantly increased when 1938 was added to lab-grown nerve cells. Results from rat models with injury to the sciatic nerve – a large nerve that controls the leg muscles – suggested that delivery of 1938 to the injured nerve increased muscle recovery, indicating nerve regeneration.

“Kinases are ‘molecular machines’ that are key to controlling the activities of our cells, and they are targets for a wide range of drugs,” said Prof. Roger Williams, co-senior author of the study and a group leader at the MRC Laboratory of Molecular Biology. “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.”

Inspiration for new therapies

“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, while also crossing boundaries between academia and industry,” said Prof. Bart Vanhaesebroeck, co-senior author of the study and professor of cell signaling at the UCL Cancer Institute. “'Blue sky’ research of this kind is difficult to get funding for in a world of increasing specialization, but hopefully this project can provide something of a model for future ambitious research.”

Based on these encouraging results, 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 investigating whether PI3K activators could be used to help treat central nervous system damage due to spinal cord injury, stroke or neurodegenerative disease.

Reference: Gong GQ, Bilanges B, Allsop B, et al. A small-molecule PI3Kα activator for cardioprotection and neuroregeneration. Nature. 2023:1-10. doi: 10.1038/s41586-023-05972-2

This article is a rework of a press release issued by University College London. Material has been edited for length and content.