"ONE SMALL STEP ..."

Last Updated 12 August 2001

INTERNATIONAL RESEARCH NEWS:

Please note that most of the information we will publish on this page will probably be technical in nature. It will normally reflect the advances made in the name of the Spinal Cord Society and will increasingly emphasise advances made at the SCS Fort Collins Research facility. Be assured that we will make every effort to publish the very latest information irrespective of it's origin, but we may need your help from time to time. If you would like to make suggestions about our page, please email our project chairman at spinal@lionsclubtraralgon.asn.au or the site editor HERE.

FORT COLLINS LABORATORY UPDATE

The overall general goal of the lab is to combine the components of a clinical cure to the point of human trials. Therefore, one major goal of the Spinal Cord Society (SCS) Research Centre is to develop a workable cell-covered bridge to support regeneration in the chronic cord. But, several components are required and not all of these are now ready. They include the polymer bridging material, which has been acquired and is ready to go, and methods of making remaining cells at the injury site conducive to axonal regrowth. The latter component is not yet completed. Other goals include optimising the conversion of other cells into suitable autologous stem cells, neurons, different types of supporting glial cells, and using this and other information to better overcome scar inhibition. This work is well underway. Still another part of the program right now is to identify tissue easily obtainable from the same patients to be treated, and learning how to isolate and culture neuronal cells from it for transplant. Some progress has been made here but more is needed.

Another part of this combination effort is to perfect the liposome delivery system and humanize it. It will mean continued testing with what has been developed in Alaska, Estonia and the Centre. So far, the system works very well in the test tube but when tried in animals does not. To humanize the system, that is make it usable for humans, human antibodies will be incorporated into what SCS has already developed. The approach will be non-toxic and so far excellent results have been obtained in that part of it. The whole idea is to be able to transfect (or inject) whatever is needed into cells so as to alter them to do or become what is desired.

All this is not easy, but at least it is ongoing practical combinations targeted right on solving the complex problem of chronic spinal cord injury, and not just talk about possibilities or working on another goal instead.

We will have brief monthly updates on each phase of work in the Centre laboratories and at 6 month intervals there will be longer, more detailed reports. In simplest terms, the basic problems, which must be solved, are about as follows:

1) Obtaining useful autologous cells. Should the right stage embryonic cells become available on a large scale and if they prove safe and non-rejecting, we will use those also, but all along SCS has believed that adult, or autologous stem cells may prove the best because of their automatic lack of any possible rejection. However attractive embryonic cells of the right stage may be, but no one knows for sure yet that they won't reject down the line. It would never do to find out too late. Nevertheless, SCS will continue to keep its options open. Cure, not politics or religion, is our main objective. And so far as we can tell it is possible to obtain usable embryonic stem cells without violating laws or ethics.

2) Using what has been learned about the chronic scar and how to effectively disrupt it to build this portion of an effective combination clinical treatment.

3) Changing stem cells into those types needed.

4) Developing various models of the polymer bridge to determine which is the best.

5) Finding which type of tissue is best to use as a source of stem cells from the same patient.

6) Perfecting and humanizing the non-toxic liposome delivery system.

7) Perfecting methods of up regulating regeneration from both remaining cells and those transplanted in a bridge.

There are now 4 Ph.D.s in the Centre and by August there will be five plus assistants. Many trials are already underway with more planned. The Centre lab is extremely well equipped.

REPORT FROM THE CELL BIOLOGY UNIT

It has been a busy spring in the SCS Research Centre in Fort Collins. Since February the research team has had their hands full creating a functional research laboratory that can now welcome newcomers with the pioneering front line research environment The units for systems biology, cell biology and molecular biology are operating in an exciting mode of a team work. Each unit carries the responsibility its progress, and all the work of individual units will be combined to solve the problems of chronic spinal cord injury.

The goal of the Cell Biology Unit is to create optimal cell types capable of modifying the scar tissue and providing a substrate for regenerating axons in the spinal cord. Even given that some neurons have an inherent ability to grow, their axons fail to cross over a site of injury because of the inhibitory nature of the scar. Different forms of glial cells vary in their function. Following injury, a glial cell forms the glial scar which is inhibitory to axons, but during development (embryonic stage) a different type of glial cell is found that supports axon growth. To be able to modify these latter cells and use them in a really controlled way we need a more complete understanding of the difference in biology between embryonic (developing) and reactive (scar) astrocytes. In a living organism, these cells receive signals from other cells inside the spinal cord. And these signals cause changes in the way the cells behave, altering their shape, their membrane characteristics, and the way they interact with other cells. The signals and the way a signal is detected by a cell change during development. We are especially interested in the surface characteristics of young cells, molecules that are not found on the surface of adult cells.

Currently, there are several different cell types growing in the Centre laboratory. These cells will be used to find ways to alter their axon-supporting capacities. Since not only one, but several different factors act in the play, we will look at them all. These factors include surface molecules, growth factors, cytokines, and factors modifying gene expression. By understanding the biology behind the difference between embryonic versus a mature astrocytes, we will be in a better position to create a cell environment that supports rather than inhibits the axonal re-growth of adult injured neurons. Dr Tuija Nordstrom, Research Scientist, SCS Research Centre.

REPORT FROM ESTONIA

At the suggestion of Dr. Neuman, the Spinal Cord Society (SCS) has pursued supplementary work in Estonia. Much of this has been an effort to provide better components for the liposome delivery system particularly the guides to targets. These reports are highly technical and so for convenience of interested readers have been shortened and summarized here. The general purpose has been to make the liposomes a more efficient delivery system for getting genetic material into cells so as to convert them into other types of desired cells. This is being done for both neurons and glial cells. The process produced no cancer.

In vivo testing of the effect of DNA recombination and repair factors on stable integration of introduced DNA into neurons has also been part of this as has humanization of immunoliposomes. For the latter, human antibodies against human neurons and glial cell surface antigens have been generated for immunoliposome targeting.

In liposome targeting of the right cells, the antibodies generated recognized cell surface antigens in the CM neurons and glial cells. This is a very difficult and complicated task, so what starts out with a lot of possibility often comes down in the end to only a very few antibodies which are useful for the purpose. So far, about tour useful screens have been reported to SCS.

To date, the transfection level (success) using liposomes has not been as high as desired. By producing move types of antibodies we have hoped to stimulate clinically useful stable integration of genes in vivo in rat CNS. To date, over-expression of several DNA repair and recombination factors does the job in the lab dish (in vitro), but in vivo success needs improvement. There is no point in developing something if it isn't usable.

Over 140 animal tests have been done and it is reported that these transfection experiments show that over-expression of DNA repair and recombination factors results in the stable integration of co-transfected reporter genes. Also shown is that such factors differ in their effect on stable integration. Some are more effective than others, some combinations even toxic. One especially bright spot is that deliberate over-expression of DNA repair and recombination factors in adult rat brain don't produce any tumours, which is good news.

The above articles appeared in the official Newsletter of the Spinal Cord Society (SCS). If you want the full text or further information, please contact the SCS on the links appearing below or in the "Want More Information" box to the left of this page.

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