Summary: Researchers report that a brain-penetrant experimental drug being developed as a cancer therapy can promote regeneration of damaged nerves and restore function after spinal cord injury in preclinical models.
Source: University of Birmingham
Overview
Scientists at the University of Birmingham have demonstrated in laboratory and animal studies that AZD1390, an orally available, brain-penetrant candidate drug under investigation for cancer, can encourage nerve regeneration and recovery of function following spinal cord injury (SCI). The findings, published in Clinical and Translational Medicine, show that AZD1390 inhibits a DNA damage response pathway in neurons, stimulates neurite outgrowth in culture, and promotes axon regrowth and restored electrical conductance across spinal lesions in preclinical models.
These results follow a separate study from the same research group showing that another investigational compound, AZD1236, reduced tissue damage after spinal trauma by limiting inflammatory responses. Both studies were supported through AstraZeneca’s Open Innovations Programme, which makes compounds and research tools available to the scientific community to accelerate translational research.
Mechanism and pharmacology
AZD1390 is a selective inhibitor of the ataxia–telangiectasia mutated (ATM) protein kinase, a central regulator of the cellular DNA damage response (DDR). The DDR is activated by DNA lesions such as double-strand breaks (DSBs), which are observed in a range of cancers and can also arise after spinal cord injury. In oncology research, inhibiting ATM-dependent signalling can sensitize cancer cells to radiation by preventing effective DNA repair. The University of Birmingham team hypothesised that a similar persistent DDR activation in injured neurons could impede recovery and that blocking ATM signalling might instead permit repair and regeneration.
In vitro experiments showed that AZD1390 engaged and suppressed its intended target in neurons and promoted dorsal root ganglion neuron (DRGN) neurite outgrowth. In animal models of SCI, oral administration of AZD1390 produced measurable suppression of the ATM kinase pathway, stimulated axon regeneration beyond the lesion site, and restored the ability of regenerated axons to conduct electrical signals across the injury. These biological effects correlated with substantial improvements in sensory and locomotor performance in treated animals.
Preclinical outcomes and potential
Professor Zubair Ahmed, from the Institute of Inflammation and Ageing, and Dr Richard Tuxworth, from the Institute of Cancer and Genomic Sciences, report that animals treated with AZD1390 showed marked recovery of sensory and motor abilities. In the study, treated animals were described as becoming difficult to distinguish from uninjured controls within four weeks after injury. The researchers emphasise that these are preclinical results and that AZD1390’s prior development for cancer may facilitate faster progression toward clinical testing for spinal cord injury because safety and pharmacology data already exist.
Dr Tuxworth noted that repurposing an existing investigational compound could shorten the time required to reach human trials compared with developing a completely new drug. The research team and University of Birmingham Enterprise have also filed a patent application covering inhibition of the ATM/Chk2 DNA damage response pathway by compounds such as AZD1390 as a potential therapeutic strategy to promote nerve repair.
Safety, administration and next steps
AZD1390 is orally bioavailable and brain-penetrant, properties that supported its selection for the study. The authors report a favourable preclinical safety profile in the context of these experiments and highlight the simplicity of oral administration as an advantage for potential clinical use. As AZD1390 remains in clinical development for oncology indications, further work will be required to validate efficacy and safety specifically for spinal cord injury in humans.
Conclusion
These preclinical findings identify ATM inhibition by AZD1390 as a promising strategy to promote axon regeneration and functional recovery after spinal cord injury. The research supports further investigation into whether repurposing this brain-penetrant ATM inhibitor could translate into a new therapeutic approach for patients with SCI, while acknowledging that clinical trials will be required to confirm benefit and safety in humans.
About this SCI and pharmacology research news
Author: Ruth Ashton
Source: University of Birmingham
Contact: Ruth Ashton – University of Birmingham
Image: The image is credited to magicmine
Original Research: Open access. “The brain penetrant ATM inhibitor, AZD1390, promotes axon regeneration and functional recovery in preclinical models of spinal cord injury” by Ahmed Z, Tuxworth RI. Clinical and Translational Medicine
Abstract
The brain penetrant ATM inhibitor, AZD1390, promotes axon regeneration and functional recovery in preclinical models of spinal cord injury
This study demonstrates that AZD1390, an orally bioavailable, brain-penetrant, potent, and highly selective inhibitor of ataxia–telangiectasia mutated (ATM), promotes dramatic recovery after spinal cord injury (SCI). AZD1390 engaged and suppressed its target and promoted dorsal root ganglion neuron (DRGN) neurite outgrowth in vitro and stimulated axon regeneration after SCI in vivo, with the recovery of conductance across the lesion site and leading to notable improvements in sensory and locomotor function. AZD1390 is currently in clinical development for cancers. The simple oral administration route and encouraging safety profile suggest AZD1390 could be explored as a potential therapy to promote functional recovery after SCI in patients.