21 July 2009

A rescue for spinal cord injuries?

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New stem cells techniques open exciting perspectives in the treatment of severe spinal cord injuries, and give hopes to cure paraplegia in humans

Spinal cord injuries cause myelopathy or damage to white matter or myelinated fiber tracts that carry signals to and from the brain. It also damages gray matter in the central part of the spine, causing segmental losses of interneurons and motorneurons. Spinal cord injury can occur from many causes, including traumas (such as automobile crashes, falls, etc.), tumors, ischemia resulting from occlusion of spinal blood vessels, developmental disorders, neurodegenerative diseases, (such as Friedreich's ataxia, spinocerebellar ataxia), demyelinative diseases, such as multiple sclerosis, transverse myelitis, (resulting from spinal cord stroke, inflammation, or other causes), vascular malformations.
Knowing the exact level of the injury on the spinal cord is important when predicting what parts of the body might be affected by paralysis and loss of function. The exact effects of a spinal cord injury vary according to the type and level injury, and can be organized into two types:

  • In a complete injury, there is no function below the "neurological" level, defined as the lowest level that has intact neurological function. If a person has some level below which there is no motor and sensory function, the injury is said to be "complete". Recent evidence suggest that less than 5% of people with "complete" spinal cord injury recover locomotion.
  • A person with an incomplete injury retains some sensation or movement below the level of the injury. Recent evidence suggest that over 95% of people with "incomplete" spinal cord injury recover some locomotory ability.

In addition to a loss of sensation and motor function below the point of injury, individuals with spinal cord injuries will often experience other complications of spinal cord injury: bowel and bladder malfunctions, sexual dysfunction, a loss of breathing, inability or reduced ability to regulate heart rate, blood pressure, sweating and hence body temperature, etc.
According to the “International Campaign for Cures of Spinal cord Injury Paralysis” (ICCP), every year over 130 000 people worldwide survive a traumatic spinal cord injury (SCI) leading to permanent paralysis and a lifetime with disability. About half of these injuries are the result of road accidents and most occur at a young age. Thus, with an average age at injury of 33,4 years and a nearly normal life expectancy due to advances in health care, it is clear that the population of people living with SCI is steadily increasing around the world. It is estimated that by 2005 over 2.5 million people worldwide will be living with SCI induced paralysis. In Europe, there are approximately 330,000 people suffering from SCI with more than 10,000 new cases occurring each year.

The costs of SCI induced paralysis for the society and the individuals are considerable. For lack of cure, present reality is that interdisciplinary rehabilitation is the only effective treatment that can be provided. Each year more than 4 billion dollars are spent in the management and care of SCI patients according to a recent report from the Council of Europe. Finally, these numbers do not take into account the social and psychological costs for the affected individuals and their families such as dependency in everyday activities, loss of employment and social status.

Treatment options for acute, traumatic non-penetrating spinal cord injuries include giving a high dose of methylprednisolone within 8 hours of injury. The recommendation is primarily based on the National Acute Spinal Cord Injury Studies (NASCIS) II and III however is disputed. Scientists are investigating many promising avenues of treatment for spinal cord injury. Thousands of articles in the medical literature describe work, mostly in animal models, aimed at reducing the paralyzing effect of injury to the spinal cord and promoting regrowth of functional nerve fibers. Despite the devastating effects of the condition, commercial funding for spinal cord cure research is limited, owing primarily to the small size of the population of potential beneficiaries and spinal cord injuries have long been regarded as intractable, largely due to the alleged inability of the central nervous system (CNS) to regenerate. Despite this, a number of experimental treatments have reached controlled human trials. In addition, nerve protection and regeneration strategies are being studied in more common conditions like Alzheimer's Disease, Parkingson's Disease and Multiple Sclerosis. There are many similarities between these neurodegenerative diseases and spinal cord injuries, as this research adds considerable new information relevant to spinal cord injury treatment.

Advances in the science of spinal cord injury treatment are newsworthy, and considerable media attention is drawn towards new developments. Aside from the use of methylprednisolone, none of these developments have reached even limited use in the clinical care of human spinal cord injury. Around the world, proprietary centers offering stem cell transplants and treatment with neuroregenerative substances are fueled by glowing testimonial reports of neurological improvement. Independent validation of the results of these treatments is mostly lacking. However, in January 2009, a pharmaceutical company received FDA clearance to begin human safety testing of its stem cell treatment candidate, on newly injured patients with complete thoracic injury. A diverse array of other treatments are being researched, including biomaterial solutions, cell replacement therapies, and electronic stimulative devices.

This is where RESCUE comes in. RESCUE is a highly innovative project aiming to pave the way toward clinical trials for stem cell therapy in Spinal Cord Injury (SCI) repair. The project is funded by the European Commission FP6 research programme, and combines the expertise of stem cell biologists as well as experts in spinal cord pathology from 9 European research groups.

RESCUE’s objective is to translate experimental studies using human stem cells in preclinical animal models into the clinic. This will be achieved through the elaboration of a series of therapeutic tools for stem cell therapy to be used in a wide variety of clinical paradigms of SCI.

Spinal cord lesions represent an ideal model for the development of regenerative therapy for traumatic lesions of the central nervous system (CNS), as they are more prone to precise functional characterization and follow-up than brain injuries. Preclinical results obtained in the context of RESCUE can therefore be used as templates for the elaboration of therapeutic strategies whose application should be broadened to other CNS traumatic damages, such as traumatic brain injuries and stroke.

The consortium has been constituted in order to bring together participants whose skills come from two different areas of research, stem cell biology on the one hand, and spinal cord pathology on the other hand. RESCUE focuses on the combination of the most efficient technologies to direct the fate of intrinsic, as well as extrinsic stem cells, and/or their transformation, in order to obtain appropriate cell types at the right time and in the right place, to promote repair of the injured spinal cord. The final aim of the RESCUEproject is to be able to propose clinical trial protocols appropriate for the treatment of SCI.

To reach this goal, the RESCUE project investigates a number of different approaches that are currently available to try to restore function of the injured spinal cord through the use of human stem cells from bone marrow and the central nervous system. These approaches include:

  • Enhanced regeneration of neurons and axons in the spinal cord through increased availability of axon growth-permissive molecules and/or trophic agents produced by stem cells or their progeny. Such molecules may be produced by unmodified cells or by cells specifically engineered to do so.
  • The regeneration/restoration of function by supporting and monitoring the activation of intrinsic spinal cord stem cells.
  • The restoration of function after replacement of the damaged cells following local grafting.
  • The use of stem cells during the acute phase (within one week of the injury in man) to reduce inflammation and secondary degeneration in the spinal cord. This also reduces the formation of the scar tissue which constitutes a major barrier to axonal regrowth.

As Spinal Cord Injuries are extremely complex, it is necessary to investigate a wide source of stem cells, since individual sources might have an application in specific pathological situations.

To give an example of results of the RESCUE project, Jean-Philippe Hugnot (teacher-researcher at the University of Montpellier) Alain Privat (Inserm research director) Luc Bauchet (neurosurgeon) and their colleagues at Inserm Research Unit 583 have for the first time demonstrated in 2008 the presence of neural precursor cells in the adult human spinal cord. The use of these stem cells for therapeutic purposes could potentially contribute to repairing the spinal cord of persons suffering from a traumatic injury, as well as in the case of a degenerative disease involving the motor neurons.

So RESCUE helps to pave the way to a rescue of spinal cord injury patients and maybe in a near future, help will be at hand.

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