Gene therapy for spinal cord injury and disease [In Process Citation]
J Spinal Cord Med 2002 Spring;25(1):2-9 (ISSN: 1079-0268)
Poulsen DJ; Harrop JS; During MJ
University of Montana, Department of Pharmaceutical Sciences, Missoula 59812-1552, USA. Poulsen@selway.umt.edu.
An incomplete understanding of the pathological processes involved in neurodegeneration and dysfunction of spinal cord injuries and diseases makes these disorders difficult to treat. Repair of damaged or genetically impaired spinal cord also has been limited by the complexity, cellular heterogeneity, and relative inaccessibility of the tissue. Thus, therapeutic options for the treatment of either chronic spinal cord diseases such as amyotrophic lateral sclerosis or acute spinal cord injuries have been rather limited. Potential new therapeutic targets are being identified as our understanding of the molecular pathology involved in neural injury and regeneration increases. Recent advances in gene transfer techniques have made gene therapy a more realistic and viable strategy for the treatment of a broad range of spinal cord disorders. This review summarizes the current state of knowledge regarding the limitations and recent advances in gene therapy and potential application of this technology toward spinal cord injury and disease.
[This message was edited by Wise Young on May 04, 2002 at 12:09 PM.]
04-24-2002, 02:36 PM
Max, if you post articles or abstracts... can you enter a brief description and why you want to post it in the header, and the actual article with the URL address to the body of the message? Thanks. Wise.
04-24-2002, 03:09 PM
i have just heard the same thing from a person at the reeve's
foundation. the primates studies will lead the way.
gene therapy has been around for over 25 years, and now
beginning to show success in animals. max,dr.wise how can we
find out more...........
04-25-2002, 09:02 AM
Perry, in spinal cord injury, there are two issues. The first is identification of beneficial (and deleterious) gene expression that can and should be manipulated in order to improve recovery, regeneration, remyelination. There are currently many laboratories systematically studying animal spinal cord injury models to identify regeneration-associated genes (RAGs), pain-associated genes (PAGs), neuroprotection-associated genes (NAGs), myelination-associated genes (MAGs), etc. Once identified, the expression of these genes can then be boosted or blocked in the spinal cord.
The second issue is the mechanism of changing gene expression. Gene therapy today is being carried out in several ways:
• Transgenic - the genes of an egg or sperm are modified and the subsequent organism then has a knockout (deleted), knockin (inserted), or dominant negative (an interfering gene) added. This is currently not an option for adult.
• In vivo transfection - the gene is inserted into certain cells by virus, liposomes, or other vectors. The viral method is the most efficient and popular at the present but got into trouble recently, particularly adenovirus (the common cold virus), because it initiated fatal inflammation in one patient (Jesse Gelsinger). Many companies have touted other non-viral means of inserting genes that are generally less efficient but presumably safer.
• Ex vivo transfection and implantation of transfected cell - specifically cells can be removed from the body, transfected so that they express certain gene products, and then implanted back into the body. Actually, the first use of this technology in the CNS was for spinal cord injury (Tuszynski, et al.)
An alternative and growing approach to manipulating gene expression is with drugs. A large number of drugs and factors are known to turn off and on certain genes. For example, the tetracycline antibiotics are known to turn on certain genes. Likewise, there are many so-called nuclear factors that go into a cell and turn on genes, i.e. NF-kappa B is the factor that turns on inflammatory genes.
There is really no magic about gene expression. We just have much more powerful tools that allow us to measure and manipulate gene expression. So, once we know which genes we want to turn on and which to turn off or modulate, it can and will be done. Unfortunately, as a recent report in the Wall Street Journal suggests, the human genome project has not yielded a huge number of treatments for the pharmaceutical industry.
Despite massive investments, the number of drugs that have been approved by the FDA has fallen in the past three years compared to previous years. The reason is that people were expecting knowledge of the human gene to produce new drugs. They had not realized that the knowledge has produced the possibility of many drugs but the same amount of work and information must be gathered about each candidate drug before it can be successfully taken to clinical trial. Thus, the investment did not reduce the expense or time in developing the drugs. It just increased the number of potential drug candidates.
One of the most interesting outcomes of the human genome project is that is has shown us how similar humans are to other animals. I suspect that primate experiments will not be essential for moving all therapies into clinical trials. Scientists are working very hard to develop surrogate measures, using human cell cultures (stem cells, etc.) that allow testing of therapies without doing as many large animal experiments. Of course, the FDA continues to require large animal safety (toxicity) studies before clinical trial but every effort is being made to reduce the number of animals required.