039: Repair of damage to the nervous system
Date: Mon Feb 27 13:17:03 GMT 2006
When the brain or spinal cord is damaged in mammals, including humans, the result is disability, often including paralysis of part of the body, loss of sensation and loss of mental ability. The work in this project aims to find treatments for bringing back useful function to patients with damage to the brain, spinal cord, and peripheral nerves.
Damage to the nervous system kills nerve cells, cuts the nerve fibres that connect nerve cells together, and removes the insulating myelin that allows nerve fibres to conduct impulses. These together lead to the loss of sensation, paralysis and loss of mental ability that follow spinal cord injury, stroke, Alzheimer’s disease and other conditions. Some parts of the body have the ability to heal and replace damaged tissue. In the nervous system healing is very limited. Nerve cells that are lost are not replaced, replacement of insulating myelin often fails, and nerve fibres cannot regenerate in the brain or spinal cord. Patients may show partial recovery after some conditions such as stroke. This is through a process known as plasticity, in which the brain and spinal cord can readjust their wiring and connections to compensate for the lost function. However plasticity is very limited in adults, although it is much more effective in young children. The reasons for the inability of the nervous system to heal itself are starting to be understood. Lost nerve cells are not replaced partly because the brain lacks sufficient stem cells in the right place, and because the adult brain has lost much of the ability to direct stem cells to differentiate into the type of nerve cells that have been lost. Nerve fibre regeneration fails because of the scar tissue that forms at sites of injury which acts as a barrier, and because there are various molecules that inhibit nerve fibre regeneration in the nervous system. Remyelination fails because the damaged nervous system does not give the right signals to the precursor cells that can make new myelin. Plasticity is lost in adults because inhibitory molecules are placed around nerve cells that prevent them forming new connections after damage. In recent years treatments have started to be developed that have the ability to stimulate some of the healing processes that can bring about recovery after brain and spinal cord injury. Some of these are now entering clinical trials in human patients. The work in the licence investigates ways in which the injury and scarring response of the brain and spinal cord can be prevented, the biology of stem cell behaviour in the damaged brain and spinal cord, ways in which nerve fibres can be made to regenerate, and methods for promoting myelin repair.
The treatments that have been developed for repair in the damaged nervous system, and those currently under development, have almost all come from tissue culture studies. However it is not sensible to attempt to take treatments directly from tissue culture studies into human patients. The human nervous system is the most complex part of the body and tissue culture models can only present a very simplified form of it. Treatments that have an effect in tissue culture may not work in the whole nervous system, may have unexpected effects, and investigations are necessary to see how best to use them. However, current experience shows that treatments for the repair of the nervous system that work in animals generally work in humans.
It has been possible to make animal models of many human conditions affecting the brain and spinal cord, but to restrict the extent of damage so that the effects on animal behaviour are minor. By using sophisticated tests of animal behaviour it is possible to measure minor disabilities that are not evident during normal life, but which provide an accurate estimate of the efficacy of treatments.
The experiments involve making a small lesion under anaesthetic to the brain or spinal cord of rodents, or using animals with a genetic defect which causes them to develop a condition similar to human neurodegeneration. The animals then have regular tests of their behavioural abilities. These test the ability of the animals to make skilled movements of the forearm such as picking small food pellets out of wells, hand strength and ability to walk skilfully. Most animals then receive a treatment designed to improve their nervous system function. These are usually given into the fluid that surrounds the brain and spinal cord. The behaviour of the animals is then monitored to see whether function improves as a result of treatment. At the end of the experiment animals are killed by anaesthetic overdose, and their nervous system tissues examined to determine the effects of the treatments.
Experience has shown that it is possible to model the pathology of the human nervous system in rodents. The molecules and structures that prevent repair of the human nervous system are present in rodents, and it is considered that treatments that are successful in rodents should be successful in humans. For some treatments preliminary trials in other mammalian species may be necessary before humans are treated, but this is not a part of this licence.
The numbers of animals used is kept to a minimum by careful design of experiments, so that the behavioural tests used are very precise and repeatable and small numbers therefore give statistically significant results. The use of tissue culture models for the initial development of treatments also reduces the total number of animals that are used for experiments. The total number of animals used in the project, including animals whose tissue is used for tissue culture experiments will be about 3000 rats and 2000 mice over a five year period.
In summary:
The project addresses a problem which leads to the disability of large numbers of human patients.
A number of treatments that may allow patients to recover from brain and spinal cord damage have been developed from tissue culture models.
These treatments cannot be assessed for efficacy and safety in tissue culture models, because the nervous system is much too complex to be reproduced in tissue culture.
The treatments developed as a result of this experimental work have the potential to alleviate the suffering of millions of human patients.
