Research from the University of Birmingham, U.K., identifies new treatment target for CNS injury and neurological disease

BIRMINGHAM, England, Sept. 15, 2022 /PRNewswire/ -- Birmingham researchers have identified a potential target for drugs to treat long-term neurological conditions like Alzheimer's Disease and foster nerve regeneration in central nervous system injuries. 

Their research, published in Science Advances, is part of a workstream exploring the signalling pathways behind 'programmed cell death', which is seen in both long-term neurological conditions and spinal cord or optic nerve injuries. 

Regardless of the cause, nerve cells appear unable to fully repair this damage, and the cell's DNA damage response (DDR) system is activated. The persistent activation of this system affects nervous system function and potentially triggers programmed cell death (apoptosis).

Professor Zubair Ahmed, from the University of Birmingham's Institute of Inflammation and Ageing, and Dr Richard Tuxworth from the Institute of Cancer and Genomic Sciences, set out to elucidate how this takes place. 

Professor Ahmed said: "Our research started out exploring DNA damage pathways activated following nerve injury.  However, the same molecular factors feature in pathways are seen in neurodegenerative diseases, and a full understanding of these mechanisms is an important step towards identifying potential targets for drug treatments." 

Today's research paper follows two recently published studies in spinal cord injury from the same research group. These studies showed an existing drug may reduce damage after spinal cord injury, by blocking the inflammatory response in the spinal cord, and brain-penetrating candidate drug currently in development as a cancer therapy can foster nerve repair after injury.

The current study focussed on pathways that include enzymes called Checkpoint kinase 1 (Chk-1) and Checkpoint kinase 2 (Chk-2), which act as gatekeepers to the DDR system, and can be inhibited using small molecules called Checkpoint kinase inhibitors (Chk-is). 

The researchers first looked at a fruit fly model of amyloid toxicity, which occurs in neurological diseases when abnormal levels of this naturally occurring protein clump together and disrupt nerve cell function.  Here the researchers found that reducing Chk1 or Chk2 expression had a protective effect.

They then switched their attention to animal neurotrauma models of optic nerve damage and spinal cord injury. 

In optic nerve damage (which occurs in patients with glaucoma, multiple sclerosis, Alzheimer's and Parkinson's disease), the animal models showed administration of Chk-2is promoted nerve cell survival, and resulted in significant nerve regeneration with improved function of the optic nerve after injury. 

These results were mirrored in spinal cord injury, where administration into the spinal canal promoted significant regrowth of nerve cells beyond the site of the injury, and, at three weeks, a full restoration of the previously impaired sensation and movement. 

Professor Ahmed commented: "These findings are truly exciting. They support a growing body of evidence that Chk-2 kinase inhibition can be both neuroprotective, and neuroregenerative, and provides a potential target for drug treatments for neurological diseases such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis." 

Dr Tuxworth added: "This study raises the possibility of a completely new treatment strategy for a variety of neurodegenerative diseases, that is aimed at supporting nervous system function and slowing the progression of disease." 

University of Birmingham Enterprise has filed patent applications covering pathways and mechanisms disclosed in all three research papers and is now seeking investment, and partners for commercial development or licencing. 

Inhibition of Chk2 promotes neuroprotection, axon regeneration and functional recovery
4 after CNS injury is published in Science Advances, and available at https://doi.org/10.1126/sciadv.abq2611

For commercial enquiries, contact Helen Dunster, Business Development Manager, University of Birmingham Enterprise, email: H.Dunster@bham.ac.uk

About the University of Birmingham
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