Imagine if loss of function from brain injuries and central nervous system conditions could be restored through a simple alteration to existing medicines. This is what a multidisciplinary team of researchers is hoping to achieve.
The world’s population is ageing, contributing to an increase in prevalence and associated costs of central nervous system (CNS) disorders.
A significant proportion of the Australian population (around 20 per cent) is affected by a brain disease, injury or disorder such as Alzheimer’s disease, epilepsy, Parkinson’s disease, cerebral palsy and multiple sclerosis.
But CNS dysfunctions are not easily addressed, according to Professor Guangzhao Mao, Head of School and Professor at the UNSW School of Chemical Engineering.
“Medicines, whether small drug molecules, proteins or large molecules, can’t enter the brain easily,” Mao said. “They are prevented by [a membrane] called the blood brain barrier [BBB].”
While the BBB fulfils an essential purpose – preventing toxins from entering the brain – it also stops up to 98 per cent of drugs reaching the body’s most important organ.
Rather than trying to penetrate the BBB, a team of UNSW researchers – led by Mao, comprising engineers and medical professors – have explored a new pathway for drug delivery.
Retrograde motion
As a chemical engineer, Mao doesn’t often cross paths with medical researchers.
“But in a chance encounter, I spoke with an anatomy professor whose research focuses on spinal cord injuries and the difficulties of treatment,” she told create.
“If the injury is severe and higher along the spinal cord, patients become completely paralysed. And there’s no cure.”
Drugs that can help to restore some motor function through stimulating the CNS are similar to a substance very familiar to most of us – caffeine.
“When we drink a cup of coffee, caffeine interacts with the brain’s neurons that control breathing, activity and excitement levels,” she said.
But to treat spinal cord injuries, these drugs must be delivered intravenously at very high dosages. This makes treatment intolerable for patients and causes a range of adverse effects – impacting the kidney and heart, among other organs.
It’s through this conversation that the researchers decided to try out a concept using gold nanoparticles for targeted drug delivery, linking a special plant-based protein – already used to mark the paths of new neuron connections in the recovery process – to the drug.
“These proteins have [a] very specific function called transsynaptic retrograde transport,” Mao said.
While neural signals that control movement come from the brain is “forward transport”, retrograde transport has the opposite effect – taking inputs from the muscle to the brain.
“Retrograde transport proteins exist in nature, sometimes even as part of a virus,” she explained. “They have a special ability to get from the muscle nerve endings up into the nerve cells – eventually entering the neuro-spinal cord and into the brain.”
Restoring breathing function
A leading cause of death for people with spinal cord injury is losing breathing capability, with patients eventually succumbing to respiratory infections.
By attaching nanoparticles and retrograde transport protein to drugs, the team successfully delivered medicine from the nerve endings in rats’ diaphragms to the motor neurons in their spinal cords and brainstems.
“In these animal models, not only are we reducing the dosage, we have seen remarkable, long-lasting recovery in breathing that has never been achieved with just drugs alone,” Mao said.
The researchers have since developed a microfluidic cell-based model to simulate nanoparticle transport in neurons.
“We are focusing on using the cell-based model to screen our synthetic products first to accelerate our discovery,” she said.
Next, the team is aiming to gather more data on the potential toxicity of the overall drug, with the view of filing an investigational new drug application.
“That’s the first step of getting to the early stage of patient studies, which will take a couple more years.”
Should the research reach the development phase, Mao said it will extend to other CNS conditions and beyond – with the team also exploring how to optimise pain medications for patients with chronic pain.
“Using opioids for chronic pain can lead to addiction in some patients,” she said. “We’ve started a project to look at targeted delivery of pain medications, so we can use a small fraction of these drugs that will not lead to addiction in the long term.
“Many old drugs can continue to be used if we just package them cleverly so they can work as intended.”