Investigational Drug Promotes Nerve Repair After Injury - Neuroscience News

Summary: An experimental drug penetrating the brain is in development as a cancer treatment could promote regeneration of nerves damaged after spinal cord injury, researchers report.

Source: University of Birmingham

Scientists from the University of Birmingham have shown that a prospective brain-penetrating drug currently being developed as a cancer therapy could promote regeneration of nerves damaged after spinal trauma.

The study, published today in Clinical Medicine and Translationused cell and animal models to demonstrate that when taken by mouth the drug candidate, known as AZD1390, can block the response to DNA damage in nerve cells and promote regeneration of damaged nerves, thereby restoring sensory and motor function after spinal cord injury.

The announcement comes weeks after the same research team showed a different investigative drug (AZD1236) could reduce damage after spinal cord injury, by blocking the inflammatory response.

Both studies were supported by the AstraZeneca Open Innovation Program, which shares compounds, tools, technology and expertise with the scientific community to advance drug discovery and development.

AZD1390 is also being investigated by AstraZeneca to block ATM-dependent signaling and repair of DNA double-stranded cleavage (DSB), an action that sensitizes cancer cells to radiation treatment. The DNA Damage Response System (DDR) is activated by DNA damage, including DSBs in the genome, which occurs in several common cancers as well as after spinal cord injury.

Professor Zubair Ahmed, of the University’s Institute of Inflammation and Aging and Dr Richard Tuxworth of the Institute of Cancer and Genomic Sciences hypothesize that continued activation of this system may prevent recovery from spinal cord injury, and that blocking it will promote nerve repair and restore function. after injury.

Their initial study found that AZD1390 stimulated the growth of nerve cells in culture, and inhibited the protein kinase ATM pathway – an important biochemical pathway that regulates the response to DNA damage.

The researchers then used animal models to investigate the effects of AZD1390 after spinal cord injury. Here they demonstrated that oral treatment with AZD1390 resulted in significant suppression of the ATM protein kinase pathway, regeneration of nerves beyond the site of injury, and the ability of these nerves to carry electrical signals across the site of injury.

Scientists from the University of Birmingham have shown that a prospective brain-penetrating drug currently being developed as a cancer therapy could promote regeneration of nerves damaged after spinal trauma. Credit: magic mine

Professor Ahmed commented: “This is an exciting time in spinal injury research with several different investigative drugs being identified as potential therapies for spinal cord injury. We are particularly pleased that AZD1390 can be taken orally and reaches the injury site in sufficient quantities to promote nerve regeneration and restore lost function.

“Our findings suggest a remarkable restoration of sensory and motor function, and AZD1390-treated animals were indistinguishable from uninjured animals within 4 weeks of injury.”

Dr Tuxworth added: “These preliminary studies show that AZD1390 can be used as a therapy in life-altering conditions. In addition, this reuse of existing investigative drugs potentially means we can reach the clinic significantly faster than developing a new drug from scratch.”

The University of Birmingham Enterprise has filed a patent application covering the inhibition of the ATM/Chk2 DNA damage response pathway by compounds such as AZD1390, which may represent a potential therapeutic strategy to induce neuronal repair.

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About this SCI and pharmacology research news

Author: Ruth Ashton
Source: University of Birmingham
Contact: Ruth Ashton – University of Birmingham
Picture: Image credited to magic mine

Original Research: Open access.
“The brain penetrant ATM inhibitor, AZD1390, promotes axon regeneration and functional recovery in a preclinical model of spinal cord injury” by Ahmed Z, Tuxworth RI. Clinical Medicine and Translation

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Abstract

The brain penetrant ATM inhibitor, AZD1390, promotes axon regeneration and functional recovery in a preclinical model of spinal cord injury.

This study demonstrated that AZD1390, an orally available mutated ataxia-telangiectasia (ATM) inhibitor, penetrates the brain, is potent, and highly selective, promoting dramatic recovery after spinal cord injury (SCI).

AZD1390 engages and suppresses its target and promotes dorsal root ganglion neuron (DRGN) growth in vitro and stimulates axon regeneration after SCI in vivo, with restoration of conductance across the lesion site and causing remarkable improvements in sensory and locomotor function. The AZD1390 is currently in clinical development for cancer.

The simple oral route of administration and good safety profile suggest that AZD1390 is a potential new therapy to improve recovery of function after SCI in patients.

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