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R.M. Clemmons, DVM, PhD, CVA, CVFT, CAPT, USPHSR, Veterinary Category
Associate Professor of Neurology & Neurosurgery
SACS, College of Veterinary Medicine

January 2006

Dr. Clemmons has been doing a limited number of stem cell transplants, on dogs that have advanced DM, in the hopes that this treatment might help dogs with Degenerative Myelopathy. However, he has found that we cannot expect them to be the miracle that everyone thought and hoped they might be. With all that was being said about stem cells, it sounded like they would be able to recreate every organ. The answer is "No, they can’t." Stem cells can be made in the test tube to do certain things. They can be made to develop certain structures and in that sense, might be useful. However, there are a few problems. If you want to use histocompatible stem cells so that anti-rejection drugs are not also needed, they must come from the individual. Mesenchymal stem cells are able to do that. However, they are as old as the patient and therefore not as robust. They can be coaxed into becoming things, but only to a limited degree and they have limited life-span. Of course, making embryonic stem cells from the individual would be great, as mentioned in the news as of late, but that turned out to be a hoax. If you use embryonic stem cells, they are more robust, but that can lead to other problems not mentioned. So, we are probably going to try fetal stem cells to see if we can find the happy medium.

Even so, while stem cells can be found to lay down and even become neurons in some cases, no one has shown that they become functional. What is known is that certain conditions improve. What we think is happening is that the stem cells provide factors which help reduce acute problems and kick start the nervous systems ability to heal which has been impeded by the formation of glial scarring. Unfortunately, it appears that this benefit, like we see with many things, is limited. While repeated stem cell injections provide minor additional effects, they begin to wear off. Whether fetal cells will be more beneficial or whether it is only the nerve growth factors that are needed remains to be seen. Dr. Clemmons is discouraged that they did not turn out to be the "cure", but we have learned a lot and that might, in the long run, turn out to be the most important thing. We need to complete our study and since Dr. Clemmons has been open about his research findings, it is getting harder to recruit people. They know that it might not be the answer, from what we already have found.

Dr. Clemmons continues to try to find out more and better ways. At least we know that stem cell transplants have been tried and that the results show some promise even if they are not the final answer.

So, in what direction is our research headed at this moment besides looking for new treatments? One basic goal is to determine the incidence of the DRB-1 allele 11J (the change indicated by the DM Flash test) in the GSD. We will also look at a couple other regions of the DNA of dogs that we have found changes in and confirm what the DRQA and DRQB haplotypes are. It seems that looking at these other regions will help clarify the genetics of GSDM.

It is our belief that lack of a positive DM Flash test would mean that the development of GSDM would be highly unlikely. That is, if you have a negative result, you can't get the disease. On the other hand, having a positive response (in a normal dog) does not mean you will get it, but only that there is a higher risk. That is part of what we are trying to find out.

Based upon the fact that the DM Flash test represents a specific change in allele 11 and would not have been reported by the group in the UK looking at the MHC region of the canine genome, the incidence of a positive DM Flash test cannot be higher than the incidence of allele 11 in the GSD. That is 43%. However, since we know that GSDM is present in about ¼ to 1/3 of GSD with neurologic disease (posterior paresis), then it is likely that it is at least 1% (3% of GSDs presenting to university veterinary colleges have posterior paresis). The real number is somewhere in between these 2 numbers: one to 43%. Hopefully, this study will tell us for sure.

What we are really trying to do is find out the incidence of a positive response to the DM Flash test in the GSD breed. However, we also want to see if the other changes that we see are also correlated with it. Of those changes, one is a 70 BP deletion in a region of the DNA which is seen in the majority of Finnish MS patients. Dr. Clemmons has seen it in the majority of GSDM patients, too. We also will be looking at regions of the genome that are related to MS in human beings, particularly with the various types of MS (exacerbating-remitting; secondary progressive; and primary progressive). We do find that there appears to be a change in the region that is associated with primary progressive MS which we are currently characterizing. The other 2 forms are just now being looked at. DR Clemmons thinks they will be negative, since the disease fits primary progressive MS more than the other forms. This also explains the responses to medication that we have seen, too.

So, we think this is important research. Until we know the incidence of the DRB-1 change, we will not be able to know the true extent of the problem that GSDM causes. We also will not know what we can or cannot do in genetic control of the disease, and we also will not really understand the significance of the disease. Certainly on an individual basis GSDM is important, but we need to have breed significance to know how large the problem is.

If the incidence of the mutation of the allele 11 in the breed is a lower percentage of the German Shepherd Dog population, it might be possible to breed DM out of the breed. If the percentage of the German Shepherd Dog population that carries the mutation of the 11J allele is larger... well... We need to find out where we are, in relation to the percentage of dogs carrying this allele mutation before we can set a course to successfully eradicate DM from our breed. Therefore, this will be the next phase of DM research.
December 2005:

Dr Clemmons has begun stem cell transplantation of bone marrow-derived mesenchymal stem cells, in dogs with Degenerative Myelopathy. He may not be able to do this for free, either, without additional funding, but it is probably too important to wait for more funding. Sadly, there is not tons of money laying around to subsidize the work. Dr Clemmons believes he can determine safety (certainly should be from all the available human data) and may be able to get some idea about efficacy. Unfortunately, he can’t track the cells or prove he has fixed anything unless the MRI data is superb. He might get some answers down the line, but he does not want to use vector infected cells in patients until he knows for sure the vector won’t cause problems down the line. Of course, that only helps you if you do necropsies on the patients, too. His hope is that the stem cells will fix the dogs and necropsies will be a long time off. So, we are pretty excited. The dogs that have undergone the stem cell transplantation have not exhibited any problems from the procedure :)

The stem cells take a couple of appointments and Dr Clemmons will look to use it in more advanced cases (where the current medication aren’t working, yet he have confirmed the GSDM as the sole cause) initially. The first appointment is to make sure of the Dx and to collect the bone marrow. The bone marrow stem cells will be cultured and, if all goes well, then replaced in the patient (but in the CSF space) in about 3 weeks. He will then have to monitor and see how thing go. Some of this will be just observation, but EMG data will help determine if he has changed things. So, it may require a follow-up visit 2 months after transplantation. All in all it will be fairly involved and he will have to be in close touch with the owners. It is also something he wouldnt be able to do without seeing the patients. So, the owners have to be committed and also have to have the financial resources to be able to do it. He will subsidize what he can, but he needs to be offering the best he knows. He can offer his skill and compassion. That he will provide for free. He won’t charge for doing the bone marrow, but may for the tests to be sure it is the right thing and for the implantation and hospitalization. That is not small, but still a lot of savings.

Dr Clemmons can’t help everyone and he will have to be fairly selective on the imaging and stem cell studies for the moment, but the flood gates are open for sampling the DNA. If he can eventually control the costs (by volume) he might be able to use any remainder of money to help defray the costs for the stem cells.