Drug could “revolutionise” treatment of spinal cord injury

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There is currently no reparative drug available for spinal cord injury patients.
There is currently no reparative drug available for spinal cord injury patients. Treatments provide only symptomatic relief and do not tackle the underlying molecular mechanisms that cause or contribute to oedema and blood-spinal cord barrier breakdown.

British researchers have found that an existing drug may reduce damage after a spinal cord injury by blocking the inflammatory response in the spinal cord.

Research by the University of Birmingham reported this week in the journal Clinical and Translational Medicine demonstrates that AZD1236, a drug developed by AstraZeneca, can significantly reduce ‘secondary damage’ caused by the body’s response to spinal cord injury (SCI).

Researchers led by Professor Zubair Ahmed, Professor of Neuroscience and lead for the Neuroscience and Ophthalmology Section at the university’s Institute of Inflammation and Ageing, used animal models to demonstrate that AZD1236 can promote significant nerve regeneration, with a dramatic 80% preservation in nerve function following spinal cord compression injury.

Crucially, this translated into an 85% improvement in movement and sensation. These dramatic effects were observed following only three days of treatment with AZD1236, starting within 24 hours post-injury. Within three weeks, the AZD1236 treated animals showed unprecedented recovery, while controls still showed significant deficits at six weeks post-injury.

One of the key drivers of SCI secondary damage is a breakdown of the blood-spinal cord barrier (BSCB). This results in oedema (excess fluid build-up around the spinal cord) and triggers an inflammatory response that can ultimately hinder the healing process, and lead to nerve cell death.

AZD1236 is a potent and selective inhibitor of two enzymes, MMP-9 and MMP-12, which are implicated in the inflammatory process.

The researchers demonstrated that AZD1236 halts SCI-induced oedema, and reduces BSCB breakdown and scarring at the site of the injury. They also examined the effect of AZD1236 dosing on MMP-9 and MMP-12 activity in both the bloodstream and cerebrospinal fluid, which surrounds the spinal cord.

Here they demonstrated significant suppression of enzyme activity after both oral dosing, and intrathecal dosing (injection into the spinal canal). Oral dosing reduced enzyme activity by 90% in serum, and 69-74% in the cerebrospinal fluid. Unsurprisingly, intrathecal injection delivered higher levels (88-90%) of suppression in the cerebrospinal fluid.

Further studies showed that AZD1236 suppressed the formation of pro-inflammatory cytokines (molecules that are known to contribute to the development of long-lasting neuropathic pain, which often follows SCI) by 85-95%. AZD1236 was also found to be 82% more effective at alleviating SCI-induced neuropathic pain sensitivity to cold, heat and touch when compared to currently used pain medications such as pregabalin (Lyrica) and gabapentin.

“There is currently no reparative drug available for SCI patients, treatments only provide symptomatic relief and do not tackle the underlying molecular mechanisms that cause or contribute to oedema and blood-spinal cord barrier breakdown,” Ahmed said.

“This drug has the potential to be a first-in-class treatment against some of the key pathological drivers of SCI and could revolutionise the prospects for recovery of SCI patients.”

University of Birmingham Enterprise, an end-to-end service for academic innovators, has filed a patent application covering selective combined inhibition activity or expression of both matrix metalloproteinase MMP-9 (gelatinase B) and MMP-12 (macrophage metalloelastase) after SCI or related injury to neurological tissue. Investors and partners are being sought to take the treatment to clinical trials.

The full study team comprised Ahmed, and University of Birmingham colleagues Sharif Alhajlah and Adam Thompson from the Neuroscience and Ophthalmology department at the Institute of Inflammation and Ageing, and Rebecca Fairclough, from AstraZeneca UK’s Emerging Innovations Unit.

Clinic-ready inhibitor of MMP-9/-12 restores sensory and functional decline in rodent models of spinal cord injury. Zubair Ahmed, Sharif Alhajlah, Adam M. Thompson, Rebecca J. Fairclough. Clinical and Translational Medicine, May 20, 2022.
https://doi.org/10.1002/ctm2.884

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