Drug development: Chemical brace

Journal name:
Nature
Volume:
503,
Pages:
S10–S12
Date published:
DOI:
doi:10.1038/503S10a
Published online

Drugs to protect vulnerable neurons and encourage neural circuits to reform could one day improve the outlook for patients with acute spinal cord trauma.

Treatments for patients with spinal cord injuries are scant. Doctors “kind of write off the spinal cord and then see what they can do to make life possible,” laments neuroscientist James Fawcett, chairman of the Cambridge Centre for Brain Repair in the UK. And the problems these patients experience go far beyond an inability to move. In the absence of communication with the brain, for example, the bladder can empty spontaneously or get overfilled, increasing the risk of bladder and kidney infections. “The way in which bladder control is usually done now is pretty crude; it's paralysing the bladder with botulinum toxin and then intermittent catheterization,” explains Fawcett. Catheterization itself comes with a risk of infections, but it is necessary to prevent the overfilling and spontaneous emptying of the bladder. In addition, people with spinal cord injuries often have lung infections and pressure sores on their skin.

ANDREW BAKER

Many young patients with spinal injuries also worry about problems with reproductive health. Nonetheless, women with spinal injuries can conceive children normally and give birth by Caesarean section. Some men with spinal injuries can still have sex; according to Fawcett, “Men can often get some sort of reflexive erection, but it's very unreliable.” Viagra has been important for restoring sexual function to these individuals. When that doesn't work, viable sperm can usually be obtained directly from a patient's testes.

As these examples show, a spinal cord injury can lead to a range of health problems beyond sensory and motor dysfunction. Better drugs to treat these injuries are desperately needed.

Will to thrive

Problems vary over time after an accident. For Jani Wood, the first weeks and months after the accident were the toughest. The 31-year-old suffered a neck injury to her cervical spine 11 years ago in a collision that also injured her two-year-old son. When she regained consciousness, Jani could move only her eyes. She blinked for 'yes' and 'no', and used an alphabet board to spell out words. She would get partway through a word and then the other person would forget what letters were already in place, Jani recalls with frustration. But her determination has kept her going since her injury, and Jani now has motor control throughout her head and neck, and can even speak and move her right index finger. Still, she has had many battles with infections, and was admitted to the intensive care unit with lung infections four times in the first six years after her accident.

“I didn't go through all of this to be taken out by a turnip.”

“She was sneaking food!” Jani's mum says with a look of incredulity. Small bits of food, mixed with saliva, were making their way into Jani's lungs and causing these infections. She is fed through a tube that goes directly into her stomach, but used to have little tastes on the sly. She no longer does. “I didn't go through all of this to be taken out by a turnip,” she says.

Despite the lack of treatments to restore function, Jani's list of medications stretches over four pages, and includes drugs for pain, digestion and sleep.

As Jani found, a major problem for people with spinal injuries is neuropathic pain, caused by damaged nerves that fire spontaneously. According to Julian Taylor, a researcher at the National Hospital for Paraplegics in Toledo, Spain, half or more of patients with spinal cord injuries suffer from neuropathic pain, and it reduces quality of life for about a third of those who experience it. In patients with incomplete injuries — meaning that they maintain some neural connections across the injury — the pain can result from hyperactive neurons at or below the level of the injury. For example, someone with an injury in the middle of the back might experience leg pain. In other patients, neuropathic pain is thought to originate in the brain.

Some of the leading drugs for treating neuropathic pain originated as treatments for other diseases. For example, the US Food and Drug Administration (FDA) initially approved gabapentin, marketed as Neurontin by Pfizer, as an anticonvulsant drug to treat patients with epilepsy. This drug raises the level of gamma-aminobutyric acid (GABA), which can reduce the responses of neurons. Gabapentin also reduces neuropathic pain in about a third of people with spinal cord injuries who take it. Jani has been taking this drug for years.

In 2004, the FDA approved a newer version of gabapentin, called pregabalin (marketed as Lyrica by Pfizer) for treating epilepsy and various forms of pain. This drug is now one of the first-line treatments for patients who suffer from neuropathic pain after a spinal injury. In neurons, pregabalin blocks calcium channels, impeding communication between neurons and reducing pain in some patients by as much as 50%. “You can never really get rid of 100% of pain [in these patients] but if you can get to that 30 to 50% milestone, that's clinically important,” says Taylor.

Pregabalin seems to work best for patients with some residual sensory function. “You have this initial excitability, which basically gets out of control and starts to bombard the brain with a lot of pain signals,” explains Taylor. This process is thought to result from faulty rewiring of neurons after injury, together with inappropriate activation of neurons, and causes chronic pain in many patients. Taylor is involved in a trial in which patients who have recently suffered a spinal cord injury will take pregabalin before neuropathic pain develops. In animal models, “if you block that spinal cord injury very quickly with a numbing agent, you can reduce a lot of this secondary-pain response in the brain,” says Taylor. He hopes that early treatment with pregabalin will have similar effects in patients.

Another first-line treatment for neuropathic pain in patients with spinal injuries, amitriptyline, was originally developed to treat depression. Amitriptyline inhibits the re-uptake of neurotransmitters, which transmit signals from one neuron to the next. Lowering the amount of neurotransmitter available to be released in subsequent signals can reduce depression and pain.

Protect the weak

In the hours, weeks and months after the initial trauma to Jani's spine, inflammation and internal bleeding caused even more damage. Microhaemorrhages from tears in the surrounding blood vessels released proteins into the spinal cord, where they caused inflammation and disrupted the delicate balance of normal neuronal function. Chemicals that are toxic to neurons are also released into the damaged spinal cord. For example, the blood contains high levels of sodium, which causes neurons to release calcium. In turn, the calcium makes neurons release glutamate, which is toxic to neurons at high concentrations. Drugs that prevent the sodium-dependent release of calcium might therefore be able to protect vulnerable neurons in patients with recent spinal cord injuries and prevent this sort of secondary damage from occurring.

There are encouraging developments on this front. One such drug, Riluzole, which is manufactured by Sanofi-Aventis, has been used to treat patients with the motor-neuron disease amyotrophic lateral sclerosis, otherwise known as Lou Gehrig's disease. In the first clinical trial of this drug in people with spinal injuries, patients treated with this drug had an improved rate of neurological recovery compared with historical rates1. The study also found that patients with cervical spinal injuries benefited more from the drug than did those with injuries to the lower spine.

Minocycline, an antibiotic that's been used for the past 30 years to treat acne, also shows promise for protecting neurons. Although the mechanism remains unclear, minocycline might be able to inhibit immune cells called microglia that are found in the spinal cord. “There are 'good' microglia and then there are 'bad' microglia,” says Fawcett. Minocycline, he hypothesizes, could be “diverting the inflammatory response towards the healing type of inflammation rather than the toxic type.” In a phase II trial led by neurosurgeon Steven Casha at the University of Calgary in Canada, patients who were treated with minocycline after a spinal cord injury seemed to show greater improvement in motor function than those treated with a placebo2. Like Riluzole, minocycline seems to have stronger beneficial effects in patients with cervical spinal injuries, particularly incomplete injuries, than in patients with injuries lower in the spine.

Encourage the strong

Even if secondary damage after a traumatic spinal cord injury can be reduced, nothing can prevent the neuronal damage caused by the initial trauma itself. But researchers are finding that it might be possible to use drugs to encourage damaged neurons to regrow, which could repair damaged neural circuits. That's a dramatic development: neuronal regeneration in the spinal cord was long thought to be impossible.

The key to neuronal regeneration is to block the Nogo66 receptor (NgR). A number of molecules bind to NgR, including the aptly named Nogo, which seems to prevent the regrowth of axons. In animal models, blocking Nogo increases the regrowth of axons and motor recovery after a spinal cord injury or stroke3. Novartis, a multinational pharmaceutical company headquartered in Switzerland, has undertaken a phase I trial of a monoclonal antibody, ATI355, that targets Nogo after injection into the cerebrospinal fluid during rehabilitation. Although a full analysis of the results has not yet been released, Novartis — in an investor presentation for its first-quarter results in 2013 — indicated that it intends to register this compound with the FDA sometime after 2017.

Other companies are also exploring NgR-related treatments for spinal cord injuries. For example, BioAxone BioSciences (based in Cambridge, Massachusetts) is developing BA-210, marketed as Cethrin, which inhibits a molecule inside neurons called Rho. After being activated by molecules such as Nogo, NgR, in turn, switches on Rho. The thinking is that inhibiting Rho might promote the growth of axons. Another possibility is that BA-210 might induce neural plasticity, rather than (or as well as) regrowth; neural plasticity involves changes in neuronal connections or restoration of broken connections, and can take place more quickly than regrowth of axons. In a phase I/II study of BA-210 in patients with spinal cord injuries, researchers assessed movement before and after treatment with the drug4. Based on ASIA motor scores — a 100-point scale developed by the American Spinal Injury Association — patients with thoracic injuries improved by an average of 2 points, and patients with cervical injuries improved by an average of about 19 points. Once again, the best results were in patients with injuries higher in the spine, but a larger study is needed for a statistical analysis of this treatment's effect.

Drugs such as BA-210 might also be used alongside decompression surgery — a procedure that is commonly performed within 24 hours of a spinal injury to remove anything that might put pressure on the spine, including herniated discs or blood clots. At the end of the surgery, a polymer embedded with Cethrin could be placed at the injured site. Efforts are underway to begin phase III studies of BA-210.

Help with rehab

After an injury to the central nervous system, glial cells called astrocytes are activated and form a barrier to wall off the injury. This 'glial scar' can block the regeneration of neurons, so breaking it down might allow nerves to regrow.

A key group of molecules in the glial scar are the proteoglycans — extracellular proteins that can be degraded by a bacterial enzyme called chondroitinase. Fawcett has led much of the research into the effects of chondroitinase in animal models. The enzyme can promote increased plasticity in animal models of spinal cord injury, but its functional effects seem to be limited unless specific rehabilitation is carried out at the same time5. It could be that chondroitinase makes the nervous system able to learn by removing — or at least breaking down — the glial scar, and that simultaneous rehabilitation encourages the nervous system to learn new motor skills, such as walking. “So you really want to be doing both of those at the same time,” Fawcett says.

George Hornby, a kinesiologist at the University of Illinois at Chicago, agrees. He's found that using a class of antidepressants called selective serotonin reuptake inhibitors (SSRIs) in combination with physical therapy increases strength and walking in some patients with incomplete spinal cord injuries6. In animal models of spinal cord injury, treatment with an SSRI called fluoxetine (Prozac; Eli Lilly) can improve walking and other aspects of motor function. A phase I clinical trial is underway to investigate whether SSRIs can help to improve motor function in patients with spinal cord injuries.

A complicating factor is that not all drugs that are used to treat patients with spinal cord injuries are helpful for rehabilitation. For example, pregabalin can be used to treat spasticity and pain resulting from spinal injuries, but it does so by inhibiting neurotransmission. As neurotransmission is essential for SSRIs to produce rehabilitation-driven benefits, Hornsby thinks that pregabalin might slow or limit such improvements — so his patients stop taking pregabalin during rehabilitation.

Where now?

For years, the search for better ways to treat spinal cord injuries has relied on drugs that were originally designed to treat other disorders. Fawcett thinks that is about to change: drugs that are tested in patients with spinal cord injuries might become useful as general neuroprotective treatments for conditions such as dementia. “The methodology for spinal cord–injury trials has been quite well worked out. There is less variability and it is easier to see changes than in stroke,” Fawcett says. So spinal cord injuries could be the best place to try out drugs for a range of neurological disorders. “To get a neuro treatment into the market you might want to start with trauma of the spinal cord and move on from there,” he says.

Jani's injuries occurred more than a decade ago, but treatments haven't moved on much since then. That's all set to change, and molecules such as Riluzole, BA-210 and ATI355 could become handy implements in the neurosurgeon's kit.

References

  1. Grossman, R. G. et al. J. Neurotrauma doi: 10.1089/neu.2013.2968 (2013).
  2. Casha, S. et al. Brain 135, 12241236 (2012).
  3. Kempf, A. & Schwab, M. E. Physiology 28, 151163 (2013).
  4. Fehlings, M. G. et al. J. Neurotrauma 28, 787796 (2011).
  5. García-Alías, G. et al. Nature Neurosci. 12, 11451151 (2009).
  6. Thompson, C. K. et al. J. Vis. Exp. doi: 10.3791/2148 (2011).

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  1. Megan Cully is a freelance writer based in London.

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