View of the spinal cord. Credit: Scientific Animations CC4.0
In a recent study published in Nature, researchers prevented T cells from causing the normal autoimmune damage that comes with spinal cord injury, sparing neurons and successfully aiding recovery in mouse models.
In spinal cord injury, the wound site attracts a whole host of peripheral immune cells, including T cells, which result in both beneficial and deleterious effects. Notably, antigen-presenting cells activate CD4+ T cells to release cytokines, ultimately leading to neuroinflammation and tissue destruction. This neuroinflammation is notably most pronounced during the acute phase of spinal cord injury. The problem is that these same T cells have a neuroprotective effect initially, only later developing autoimmunity and attacking the injury site.
Using single cell RNA sequencing, the researchers found that CD4+ T cell clones in mice showed antigen specificity towards self-peptides of myelin and neuronal proteins. Self-peptides have been implicated in a wide range of autoimmune conditions.
Using mRNA techniques, the researchers edited the T cell receptor, so that they shut off after a few days. In mouse models of spinal cord injury, they showed notable neuroprotective efficacy, partly as a result of modulating myeloid cells via interferon-γ.
Their findings provided insights into the mechanisms behind the neuroprotective function of injury-responsive T cells. This will help pave the way for the future development of T cell therapies for central nervous system injuries, and perhaps treatments for neurodegenerative diseases such as Alzheimer’s.
Spinal cord injury survivor is a capable and helpful big brother
Kamogelo Sodi, who was injured in a car crash when he was just six years old, says he learned valuable skills on how to regain his independence at the Netcare Rehabilitation Hospital. The teenager enjoys cooking for himself, taking care of his three younger brothers, and playing basketball when he’s not studying hard to achieve his dream of being a medical practitioner one day.
5 September 2024: At 14 years old, Kamogelo Sodi of Alberton enjoys listening to music, chatting with his friends on social media and working hard at school towards his dream of becoming a neurosurgeon one day. He cooks for himself when he’s hungry and loves looking after his three little brothers. He also likes playing basketball. The difference between him and most other teenagers is that he does all this from his wheelchair.
“Since I’ve been in a wheelchair, I’ve become more confident,” says the vivacious teenager. “I was extremely shy, and I didn’t have a lot of friends, but now I have loads of friends.”
In 2016, when he was just six years old, Kamogelo’s life changed forever. He was in a devastating car crash, which left him with fractures in the lumbar region of his spine, resulting in complete paraplegia.
Once discharged from the hospital, where he had emergency surgery, Kamogelo was sent to the Netcare Rehabilitation Hospital to learn how to cope with, as his mother Reshoketswe Sodi calls it, his new normal. He was to stay there for almost six months.
Mrs Sodi, a radiation therapist, says the enduring care of the doctors, occupational therapists and physiotherapists there helped support Kamogelo and their family on their journey towards accepting and learning to cope with this difficult transition in his life. “It was important for me that he continued his schoolwork while there. When the social worker asked me what I wanted to happen, the first thing I said was that I didn’t want to break the routine of what he had been doing and that I wanted him to continue with school.
“It’s been a struggle, but with the help of the occupational therapists and physiotherapists, it has been an easier journey. We saw real progress when they taught Kamogelo something, and he grasped it, putting all his energy into it by thinking positively about it. It’s been hard, but with the support of the team from Netcare Rehabilitation Hospital, we managed it,” she says.
“After he was discharged, initially, we lived in a flat on the seventh floor. When the lifts weren’t working, like during load shedding, I’d have to carry him upstairs on my back – there was no other way to take him up. I’m so fortunate that I had a lot of support from my family and friends who’ve been pillars of strength for us.”
Kamogelo remembers his first visit to the Netcare Rehabilitation Hospital in Auckland Park. “When I first got to the hospital, I was lost. I didn’t know how to use a wheelchair. I was still so young. But they were so kind and taught me everything I needed to know.
“At first, I struggled to move around. I battled to transfer myself from place to place, but they showed me what to do, and over time, I started getting used to it. I managed to start moving myself around, and I began to enjoy it. From that day forward, I didn’t like people pushing me around. The staff also taught me how to transfer myself from my wheelchair to the car. It was a bit difficult at first, but I learned to push myself up properly so my bottom wouldn’t scrape on the wheelchair.
“It does help you become more independent, but you must be consistent. You don’t need to complain about things, you just need to listen to the people who want to help you learn to be independent.”
Later, in 2022, when he was 12 years old, Kamogelo returned to the Netcare Rehabilitation Hospital after he developed a severe pressure sore.
Dr Anrie Carstens, a doctor at the Netcare Rehabilitation Hospital, said Kamogelo was operated on at Netcare Milpark Hospital under the care of a plastic surgeon who did a flap to close the wound. “When the doctor was happy with his progress, Kamogelo came to us to help him because you get weak after surgery. The wound had healed, but the skin was delicate, so we had a graded seating approach for him to build up his strength and so that the areas of the skin didn’t break down. Another area of focus for Kamogelo was spasticity at the ankles. We worked on relaxing the ankles to get to a ninety-degree angle so he could sit better in his chair with his feet positioned well in the footrest.”
When homesickness inevitably struck, the staff comforted Kamogelo. “I began to miss home, and I cried and said I wanted to go home. They spoke nicely to me and said they first had to help me so I could go back home with no problems so my parents wouldn’t have to worry about me because of the pressure sore.”
Kamogelo said the staff also taught him valuable techniques to help him empty his bladder and bowels and assisted him in his journey to independence. “I was worried it would be painful and was a bit hesitant to try them out. But, doing it daily helped my routine and helped me become independent.”
Charne Cox, a physiotherapist at Netcare Rehabilitation Hospital, describes Kamogelo as bubbly, intelligent and with lovely manners. “He’s so motivated and tried so hard in therapy. He manages to go to school each day, not because of us, but because of his character.”
She says as children grow, their needs change. “The pressure sore developed because his seating in his wheelchair was not adequate because he had grown so much. We collaborated with the wheelchair manufacturer to re-evaluate and reassess the wheelchair seating, and they made him a new wheelchair. He was getting heavier, and his feet weren’t in alignment, so it was trickier for him to safely transfer from the wheelchair to the bed, for instance. It was good to re-educate him on pressure relief and pressure sores. It’s vital that adolescents are taught to take responsibility for themselves.”
Cox also helped Kamogelo work towards getting his feet in a better position.
“Children are so good about learning to use a wheelchair. Kamogelo was so motivated to move and be independent. He absorbed the information we gave him to enable him to go up ramps, turn and even do wheelies because he liked to explore.
“Children want to learn and have fun. They want to be independent. It’s amazing to help give them the tools to be the best new person they can be. Unfortunately, sometimes we can’t fix the injury, but we can give them the best opportunity to be as independent as possible. It’s so satisfying to know that Kamogelo is going to school and playing basketball.”
Kamogelo is determined to pursue a career as a neurosurgeon. “As long as I follow the path that I want to do and enjoy it, I will continue pursuing that path. Academically, I was the top achiever from grade four to grade six at my school.”
When he’s not at school, he loves going around the estate he lives in, getting fresh air, and being a good big brother to his three younger brothers. “They’re a handful, but what can I say – they’re my brothers, and I love them,” he says with a laugh.
Asked who his hero is, Kamogelo is quick to say his mother and father are both his heroes. His mom clearly thinks he’s a hero too. She’s smiling as she speaks about her son. “He’s playful and has a great sense of humour. He’s helpful in the house. Instead of wanting us to help him, thanks to the skills he learned at Netcare Rehabilitation Hospital, Kamogelo always says, ‘Let me give you a hand. Let me help you.’”
5 September 2024, International Spinal Cord Injury Day is commemorated on Thursday 5 September, drawing attention to the many ways people can be affected by spinal cord injury, creating awareness of prevention, and highlighting the possibilities for a fulfilling life after injury.
According to the World Health Organization, globally, over 15 million people are living with spinal cord injuries. Most of these cases are due to trauma, including falls, road traffic injuries or violence.
Jessica Morris, an occupational therapist at the Netcare Rehabilitation Hospital in Auckland Park, says one of the most critical aspects of care for those who’ve been impacted by spinal cord injuries is the importance of successful rehabilitation through a holistic, integrated approach from a multidisciplinary team.
“Many people just think it’s just about mobility. It’s so much more than that. Rehabilitation is complex because many different areas of our patients’ lives are affected.” Morris says they are fortunate that their team has so many different practitioners who can contribute to treating spinal cord injury patients, helping them regain a level of independence, which is vital to their self-confidence and sense of empowerment.
Dr Anrie Carstens, a general practitioner with a particular interest in physical medicine and rehabilitation who practises at the Netcare Rehabilitation Hospital, says the message of Spinal Cord Injury Awareness Day has relevance all year round, as people with spinal cord injuries need to be incorporated into society.
“It’s an opportunity to tell people not to be nervous to talk to someone in a wheelchair. They’re just like you or me, and they just have special ways of moving around and managing their pain and different aspects of their bodies. With the help of proper rehabilitation, the person can be better integrated as a functional, contributing member of society.”
Dr Carstens says people should also be aware that if they or their loved ones are ever impacted by a spinal cord injury, professional support is available. “Don’t just go straight home after your hospital stay and try to do everything on your own. Instead, come to a specialised spinal cord injury unit like ours, with therapists, doctors and nursing staff who are well versed in spinal cord injury and know the finer nuances necessary to optimally treat the person and show them how best to cope with their injury.
“In the multidisciplinary approach, every practitioner has a role in getting the person back into the real world, whether it means going back home, back to school, back to work or wherever they were before their injury occurred.”
From doctors and nurses with specialised skills to physiotherapists, occupational therapists, social workers and psychologists, speech therapists, a prosthetist and dieticians, the team provides a broad person focussed rehabilitation service to both adults and children. Their aim is to optimise their patients’ independence level using specialised equipment and teaching specific techniques to help overcome the obstacles a person may face.
Dr Carstens says it’s rewarding work for the staff at the hospital, who build up enduring relationships with those they care for. “One of the highlights is to compare and see what the patient was like when you admitted them and then see on discharge how much they’ve grown, how they’ve gained confidence and become more independent. What’s even better is to see them after they’ve been discharged and observe how well they’ve coped and how they’ve integrated and adjusted to their environment. We build a relationship with our patients because they stay with us for quite a while, and we usually have checkups every year after the person is discharged, often for life. We get to see them grow and thrive outside the healthcare setting, and we need more awareness about how much it is possible for people with spinal cord injuries to achieve.”
View of the spinal cord. Credit: Scientific Animations CC4.0
Injuries, infection and inflammatory diseases that damage the spinal cord can lead to intractable pain and disability but some degree of recovery may be possible. The question is, how best to stimulate the regrowth and healing of damaged nerves.
At the Vanderbilt University Institute of Imaging Science (VUIIS), scientists are focusing on a previously understudied part of the brain and spinal cord – white matter, which is made up of axons that relay signals. Their discoveries could lead to treatments that restore nerve activity through the targeted delivery of electromagnetic stimuli or drugs.
“In the spinal cord, the white matter signal is quite large and detectable, unlike in the brain, where it has less amplitude than the grey matter (signal),” said Sengupta, research instructor in Radiology and Radiological Sciences at Vanderbilt University Medical Center.
“This may be due to the larger volume of white matter in the spinal cord compared to the brain,” he added. Alternatively, the signal could represent “an intrinsic demand” in metabolism within the white matter, reflecting its critical role in supporting grey matter.
For several years, Gore, who directs the VUIIS, and his colleagues have used functional magnetic resonance imaging (fMRI) to detect blood oxygenation-level dependent (BOLD) signals, a key marker of nervous system activity, in white matter.
Last year, they reported that when participants undergoing fMRI perform a task, like wiggling their fingers, BOLD signals increase in white matter throughout the brain.
The current study monitored changes in BOLD signals in the white matter of the spinal cord at rest and in response to a vibrotactile stimulus applied to the fingers in an animal model. In response to stimulation, white matter activity was higher in “tracts” of ascending fibres that carry the signal from the spine to the brain.
This result is consistent with white matter’s known neurobiological function, the researchers noted. White matter contains non-neuronal glial cells that do not produce electrical impulses, but which regulate blood flow and neurotransmitters, the signaling molecules that transmit signals between nerve cells.
Much remains to be learned about the function of white matter in the spinal cord. But the findings from this research may help in improved understanding of diseases that affect white matter in the spinal cord, including multiple sclerosis, Sengupta said.
“We will be able to see how activity in the white matter changes in different stages of the disease,” he said. Researchers also may be able to monitor the effectiveness of therapeutic interventions, including neuromodulation, in promoting recovery following spinal cord injury.
Fibrotic scar 14d after spinal cord injury, red – Col1a1+ perivascular fibroblast derived cells Photo: Daniel Holl
New research has found that scar formation after spinal cord injuries is more complex than previously thought. Scientists at Karolinska Institutet have identified two types of perivascular cells as key contributors to scar tissue, which hinders nerve regeneration and functional recovery. These findings, published in Natural Neuroscience, are also relevant for other brain and spinal cord injuries and could lead to targeted therapies for reducing scarring and improving outcomes.
The central nervous system (CNS) has very limited healing abilities. Injuries or autoimmune diseases like multiple sclerosis often lead to permanent functional deficits.
Regardless of the injury’s cause, the body responds by forming a boundary around the damaged tissue, which eventually becomes permanent scar tissue.
Two contributing cell types
While scar tissue seals the damaged area, it also prevents functional repair. After spinal cord injuries, scar tissue blocks the regeneration of nerve fibers that connect the brain with the body, resulting in paralysis after severe injuries.
The research team led by Christian Göritz at Karolinska Institutet has made significant progress in understanding how scar tissue forms in the CNS. The group now identified two distinct types of perivascular cells, which line different parts of blood vessels, as the major contributors to fibrotic scar tissue after spinal cord injury. Depending on the lesion’s location, the two identified cell types contribute differently.
“We found that damage to the spinal cord activates perivascular cells close to the damaged area and induces the generation of myofibroblasts, which consequently form persistent scar tissue,” explains first author Daniel Holl, researcher at the Department of Cell and Molecular Biology.
By examining the process of scar formation in detail, the researchers hope to identify specific therapeutic targets to control fibrotic scarring.
Zebrafish have a remarkable ability to heal their spinal cord after injury. Now, researchers at Karolinska Institutet have uncovered an important mechanism behind this phenomenon – a finding that could have implications for the treatment of spinal cord injury in humans.
In a new study published in Nature Communications,researchers show that the neurons of adult zebrafish immediately start to cooperate after a spinal cord injury, keeping the cells alive and stimulating the healing process.
“We have shown that the neurons form small channels called gap junctions, which create a direct connection between the neurons and enable the exchange of important biochemical molecules, allowing the cells to communicate and protect each other,” explains Konstantinos Ampatzis, a researcher in the Department of Neuroscience at Karolinska Institutet, who led the study.
The researchers will further investigate the exact mechanisms behind this protective strategy in zebrafish and hope this knowledge will lead to new ways of treating spinal cord injury in humans.
“Spinal cord injuries are a major burden for sufferers and their families,” says Konstantinos Ampatzis. “What if we could get human neurons to adopt the same survival strategy and behave like zebrafish neurons after an injury? This could be the key to developing new effective treatments.”
Conditions such as diabetes, heart attack and vascular diseases commonly diagnosed in people with spinal cord injuries can be traced to abnormal post-injury neuronal activity that causes abdominal fat tissue compounds to leak and pool in the liver and other organs, a new animal study published in Cell Reports Medicine has found.
After discovering the connection between dysregulated neuron function and the breakdown of triglycerides in fat tissue in mice, researchers found that a short course of the drug gabapentin, commonly prescribed for nerve pain, prevented the damaging metabolic effects of the spinal cord injury – though not without side effects.
Gabapentin inhibits a neural protein that, after the nervous system is damaged, becomes overactive and causes communication problems – in this case, affecting sensory neurons and the abdominal fat tissue to which they’re sending signals.
“We believe there is maladaptive reorganisation of the sensory system that causes the fat to undergo changes, initiating a chain of reactions – triglycerides start breaking down into glycerol and free fatty acids that are released in circulation and taken up by the liver, the heart, the muscles, and accumulating, setting up conditions for insulin resistance,” said senior author Andrea Tedeschi, assistant professor of neuroscience in The Ohio State University College of Medicine.
“Through administration of gabapentin, we were able to normalise metabolic function.”
Previous research has found that cardiometabolic diseases are among the leading causes of death in people who have experienced a spinal cord injury. These often chronic disorders can be related to dysfunction in visceral white fat (or adipose tissue), which has a complex metabolic role of storing energy and releasing fatty acids as needed for fuel, but also helping keep blood sugar levels at an even keel.
Earlier investigations of these diseases in people with neuronal damage have focused on adipose tissue function and the role of the sympathetic nervous system, but also a regulator of adipose tissue that surrounds the abdominal organs.
Instead, Debasish Roy, a postdoctoral researcher in the Tedeschi lab and first author on the paper, decided to focus on sensory neurons in this context. Tedeschi and colleagues have previously shown that a neuronal receptor protein called alpha2delta1 is overexpressed after spinal cord injury, and its increased activation interferes with post-injury function of axons, the long, slender extensions of nerve cell bodies that transmit messages.
In this new work, researchers first observed how sensory neurons connect to adipose tissue under healthy conditions, and created a spinal cord injury mouse model that affected only those neurons – without interrupting the sympathetic nervous system.
Experiments revealed a cascade of abnormal activity within seven days after the injury in neurons – though only in their communication function, not their regrowth or structure – and in visceral fat tissue. Expression of the alpha2delta1 receptor in sensory neurons increased as they over-secreted a neuropeptide called CGRP, all while communicating through synaptic transmission to the fat tissue – which, in a state of dysregulation, drove up levels of a receptor protein that engaged with the CGRP.
“These are quite rapid changes. As soon as we disrupt sensory processing as a result of spinal cord injury, we see changes in the fat,” Tedeschi said. “A vicious cycle is established – it’s almost like you’re pressing the gas pedal so your car can run out of gas but someone else continues to refill the tank, so it never runs out.”
The result is the spillover of free fatty acids and glycerol from fat tissue, a process called lipolysis, that has gone out of control. Results also showed an increase in blood flow in fat tissue and recruitment of immune cells to the environment.
“The fat is responding to the presence of CGRP, and it’s activating lipolysis,” Tedeschi said. “CGRP is also a potent vasodilator, and we saw increased vascularisation of the fat – new blood vessels forming as a result of the spinal cord injury. And the recruitment of monocytes can help set up a chronic pro-inflammatory state.”
Silencing the genes that encode the alpha2delta1 receptor restored the fat tissue to normal function, indicating that gabapentin – which targets alpha2delta1 and its partner, alpha2delta2 – was a good treatment candidate. Tedeschi’s lab has previously shown in animal studies that gabapentin helped restore limb function after spinal cord injury and boosted functional recovery after stroke.
But in these experiments, Roy discovered something tricky about gabapentin: the drug prevented changes in abdominal fat tissue and lowered CGRP in the blood, in turn preventing spillover of fatty acids into the liver a month later, establishing normal metabolic conditions. But paradoxically, the mice developed insulin resistance, a known side effect of gabapentin.
The team instead tried starting with a high dose, tapering off and stopping after four weeks.
“This way, we were able to normalise metabolism to a condition much more similar to control mice,” Roy said. “This suggests that as we discontinue administration of the drug, we retain beneficial action and prevent spillover of lipids in the liver. That was really exciting.”
Finally, researchers examined how genes known to regulate white fat tissue were affected by targeting alpha2delta1 genetically or with gabapentin, and found both of these interventions after spinal cord injury suppress genes responsible for disrupting metabolic functions.
Tedeschi said the combined findings suggest starting gabapentin treatment early after a spinal cord injury may protect against detrimental conditions involving fat tissue that lead to cardiometabolic disease – and could enable discontinuing the drug while retaining its benefits and lowering the risk for side effects.
In this study, spinal cords that associated limb position with an unpleasant experience learned to reposition the limb after only 10 minutes, and retained a memory the next day. Spinal cords that received random unpleasantness did not learn. Credit: RIKEN
Researchers in Japan have discovered the neural circuitry in the spinal cord that allows brain-independent motor learning. This study by Aya Takeoka at the RIKEN Center for Brain Science and colleagues found two critical groups of spinal cord neurons, one necessary for new adaptive learning, and another for recalling adaptations once they have been learned. The findings, published in Science, could help scientists develop ways to assist motor recovery after spinal cord injury.
It has been long been known that motor output from the spinal cord can be adjusted through practice even without a brain. This has been shown most dramatically in headless insects, whose legs can still be trained to avoid external cues. Until now, no one has figured out exactly how this is possible, and without this understanding, the phenomenon is not much more than a quirky fact. As Takeoka explains, “Gaining insights into the underlying mechanism is essential if we want to understand the foundations of movement automaticity in healthy people and use this knowledge to improve recovery after spinal cord injury.”
Before jumping into the neural circuitry, the researchers first developed an experimental setup that allowed them to study mouse spinal cord adaptation, both learning and recall, without input from the brain. Each test had an experimental mouse and a control mouse whose hindlegs dangled freely. If the experimental mouse’s hindleg drooped down too much it was electrically stimulated, emulating something a mouse would want to avoid. The control mouse received the same stimulation at the same time, but not linked to its own hindleg position.
After just 10 minutes, they observed motor learning only in the experimental mice; their legs remained high up, avoiding any electrical stimulation. This result showed that the spinal cord can associate an unpleasant feeling with leg position and adapt its motor output so that the leg avoids the unpleasant feeling, all without any need for a brain. Twenty-four hours later, they repeated the 10-minute test but reversed the experimental and control mice. The original experimental mice still kept their legs up, indicating that the spinal cord retained a memory of the past experience, which interfered with new learning.
Having thus established both immediate learning, as well as memory, in the spinal cord, the team then set out to examine the neural circuitry that makes both possible. They used six types of transgenic mice, each with a different set of spinal neurons disabled, and tested them for motor learning and learning reversal. They found that mice hindlimbs did not adapt to avoid the electrical shocks after neurons toward the top of the spinal cord were disabled, particularly those that express the gene Ptf1a.
When they examined the mice during learning reversal, they found that silencing the Ptf1a-expressing neurons had no effect. Instead, a group of neurons in the ventral part of the spinal cord that express the En1 gene was critical. When these neurons were silenced the day after learning avoidance, the spinal cords acted as if they had never learned anything. The researchers also assessed memory recall on the second day by repeating the initial learning conditions. They found that in wildtype mice, hindlimbs stabilised to reach the avoidance position faster than they did on the first day, indicating recall. Exciting the En1 neurons during recall increased this speed by 80%, indicating enhanced motor recall.
“Not only do these results challenge the prevailing notion that motor learning and memory are solely confined to brain circuits,” says Takeoka, “but we showed that we could manipulate spinal cord motor recall, which has implications for therapies designed to improve recovery after spinal cord damage.”
In a new study using mice, neuroscientists have uncovered a crucial component for restoring functional activity after spinal cord injury. In the study, published in Science, the researchers showed that re-growing specific neurons back to their natural target regions led to recovery, while random regrowth was not effective.
In a 2018 study in Nature, the team identified a treatment approach that triggers axons to regrow after spinal cord injury in rodents. But even as that approach successfully led to the regeneration of axons across severe spinal cord lesions, achieving functional recovery remained a significant challenge.
For the new study, the team of researchers from UCLA, the Swiss Federal Institute of Technology, and Harvard University aimed to determine whether directing the regeneration of axons from specific neuronal subpopulations to their natural target regions could lead to meaningful functional restoration after spinal cord injury in mice. They first used advanced genetic analysis to identify nerve cell groups that enable walking improvement after a partial spinal cord injury.
The researchers then found that merely regenerating axons from these nerve cells across the spinal cord lesion without specific guidance had no impact on functional recovery. However, when the strategy was refined to include using chemical signals to attract and guide the regeneration of these axons to their natural target region in the lumbar spinal cord, significant improvements in walking ability were observed in a mouse model of complete spinal cord injury.
“Our study provides crucial insights into the intricacies of axon regeneration and requirements for functional recovery after spinal cord injuries,” said Michael Sofroniew, MD, PhD, professor of neurobiology at the David Geffen School of Medicine at UCLA and a senior author of the new study. “It highlights the necessity of not only regenerating axons across lesions but also of actively guiding them to reach their natural target regions to achieve meaningful neurological restoration.”
The authors say understanding that re-establishing the projections of specific neuronal subpopulations to their natural target regions holds significant promise for the development of therapies aimed at restoring neurological functions in larger animals and humans. However, the researchers also acknowledge the complexity of promoting regeneration over longer distances in non-rodents, necessitating strategies with intricate spatial and temporal features. Still, they conclude that applying the principles laid out in their work “will unlock the framework to achieve meaningful repair of the injured spinal cord and may expedite repair after other forms of central nervous system injury and disease.”
Researchers in the UK have evaluated a potential drug for the treatment of spinal cord injury (SCI), which could potentially regrow damaged nerves, and found it to be safe and tolerable. The results of their Phase 1 clinical trial were published in British Journal of Clinical Pharmacology and evaluated the KCL-286 drug, which activates retinoic acid receptor beta (RARb) in the spine to promote recovery.
There are no licensed drugs that can fix the adult central nervous system’s inability to regenerate. Implants have been able to restore some function, but for most, spinal cord injuries are life-changing.
Previous studies have shown that nerve growth can be stimulated by activating the RARb2 receptor, but no drug suitable for humans has been developed. KCL-286, an RARb2 agonist, was developed by Professor Corcoran and team and used in a first in man study to test its safety in humans.
The study by the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, recruited 109 healthy males in a single ascending dose (SAD) adaptive design with a food interaction (FI) arm, and multiple ascending dose (MAD) arm. Participants in each arm were further divided into different dose treatments.
SAD studies are designed to establish the safe dosage range of a medicine by providing participants with small doses before gradually increasing the dose provided. Researchers look for any side effects, and measure how the medicine is processed within the body. MAD studies explore how the body interacts with repeated administration of the drug, and investigate the potential for a drug to accumulate within the body.
Researchers found that participants were able to safely take 100mg doses of KCL-286, with no severe adverse events.
Professor Jonathan Corcoran, Professor of Neuroscience and Director of the Neuroscience Drug Discovery Unit, at King’s IoPPN and the study’s senior author said, “This represents an important first step in demonstrating the viability of KCL-286 in treating spinal cord injuries. This first-in-human study has shown that a 100mg dose delivered via a pill can be safely taken by humans. Furthermore, we have also shown evidence that it engages with the correct receptor.
“Our focus can hopefully now turn to researching the effects of this intervention in people with spinal cord injuries.”
Dr Bia Goncalves, a senior scientist and project manager of the study, and the study’s first author from King’s IoPPN said, “Spinal Cord Injuries are a life changing condition that can have a huge impact on a person’s ability to carry out the most basic of tasks, and the knock-on effects on their physical and mental health are significant.
“The outcomes of this study demonstrate the potential for therapeutic interventions for SCI, and I am hopeful for what our future research will find.”
The researchers are now seeking funding for a Phase 2a trial studying the safety and tolerability of the drug in those with SCI.
