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Neuroscientists at the University of Birmingham have found that an anticancer drug in development is capable of stimulating the regeneration of nerves damaged after spinal cord trauma. This drug, called AZD1390, was originally designed to make cancer cells more sensitive to radiation therapy.
According to the World Health Organization, between 250,000 and 500,000 people worldwide sustain a spinal cord injury each year. Most cases are due to trauma (traffic accident, fall, etc.). The symptoms (partial or total loss of sensory function and/or motor control of the extremities) depend on the severity of the injury and its exact location. Those affected are two to five times more likely to die prematurely. Unfortunately, there is currently no cure.
In fact, the treatment of spinal cord injuries is very complex, especially since the neurons of the central nervous system naturally have a low capacity for regeneration after injury. These lesions are characterized by the accumulation of unrepaired double-strand breaks in the DNA of neurons, which leads to genome instability in replicating cells and can trigger apoptosis (the self-destruction of cells). These breaks cause the activation of ATM, a protein kinase that regulates its repair.
A mechanism involved in two different conditions.
The ATM protein is capable of repairing breakages caused by physiological processes or physical aggressions, such as ionizing radiation; slows down the cell cycle of affected cells and stimulates DNA repair. If the latter is irreparable, the cell is eliminated by apoptosis.
The drug candidate AZD1390, whose development is supported by AstraZeneca’s Open Innovations program, aims to improve the efficacy of radiotherapy in cancer treatment. Its mode of action is to enter the brain, where it inhibits the ATM response mechanism to DNA double-strand breaks, damage that also occurs in several common cancers.
Because this response mechanism is apparently involved in two unrelated conditions (spinal cord injury and cancer), Prof. Zubair Ahmed and Dr. Richard Tuxworth hypothesized that persistent activation of this system may prevent nerve injury recovery and that blocking it via AZD1390 would instead promote nerve repair and restoration of sensory and motor functions.
The two researchers used cellular (spinal ganglia neurons) and animal models to test their hypothesis. Early experiments revealed that AZD1390 stimulated the growth of nerve cells in culture and inhibited the ATM protein kinase pathway. ” Treatment of spinal ganglia neuron cultures with increasing concentrations of AZD1390 from 1 to 10 nM significantly reduced levels of ATM activation, with 5 nM being the lowest and most effective dose. the researchers report. Cell survival rates exceeded 80%.
A “spectacular” recovery of sensory and motor functions
They then studied the effect of AZD1390 on mice with spinal cord injury. They were given a daily dose of 20 mg/kg of the drug. The results were particularly encouraging: Our results show a remarkable recovery of motor and sensory functions, and AZD1390-treated animals are indistinguishable from uninjured animals within four weeks post-injury. Professor Ahmed commented.
AZD1390 treatment resulted in significant inhibition of the ATM protein kinase pathway and promoted nerve regeneration beyond the injury site. The ability of these nerves to transmit electrical signals has also improved.
In both experiments, the results were similar to or better than those obtained with another ATM pathway inhibitor, called KU-60019, tested in parallel. ” AZD1390 could be a superior restorative drug for the treatment of spinal cord injuries “, conclude the two scientists.
Professor Ahmed is pleased to point out that a number of experimental drugs have already been identified as potential treatments for spinal cord injuries. But the advantage of AZD1390 is that it can be administered easily, orally, and that it already has a good safety profile. The fact that it is already tested in other conditions will allow faster access to clinical trials.
Note that this announcement comes a few weeks after the same research team showed that another experimental drug (called AZD1236), a potent and reversible inhibitor of human MMP-9 and MMP-12, can reduce the damage caused by spinal cord injury by blocking the inflammatory response.