Research Updates

Dr. Karen Munana presented her finding on the two studies EVALUATION OF LEVETIRACETAM AS ADJUNCTIVE TREATMENT FOR CANINE EPILEPSY and ASSOCIATION BETWEEN THE ABCB-1 (MDR-1) GENE AND SEIZURE CONTROL IN CANINE EPILEPSY at the American College meeting in Anaheim, CA on June 12, 2010. Below are the summaries from her findings.

Principal Investigator: Dr. Karen R. Muñana, North Carolina State University College of Veterinary Medicine
Funding: Morris Animal Foundation

The purpose of this blinded, placebo controlled clinical trial was to evaluate the safety and effectiveness of levetiracetam when used as add-on therapy in dogs with poorly controlled idiopathic epilepsy. Findings from the study suggest that levetiracetam is safe in epileptic dogs. There was no difference in incidence of side effects between levetiracetam and placebo treatment, and no changes in laboratory parameters were identified throughout the course of the study. The majority of dogs experienced a decrease in seizure frequency during levetiracetam treatment. However, the weekly seizure frequency relative to baseline decreased during both levetiracetam and placebo administration, such that a significant difference in effectiveness of levetiracetam over placebo was not observed. Levetiracetam serum levels were highly variable and did not correlate with treatment response. Further evaluation of levetiracetam as therapy for canine epilepsy is warranted.

ASSOCIATION BETWEEN THE ABCB-1 (MDR-1) GENE AND SEIZURE CONTROL IN CANINE EPILEPSY.

Principal Investigator: Dr. Karen R. Muñana, North Carolina State University College of Veterinary Medicine
Funding: Collie Health Foundation

Medically refractory seizures are a significant problem in both human and canine epilepsy. Alterations in the ABCB-1 (also known as the multidrug resistance or MDR-1) gene have been proposed to play a role in drug-resistant epilepsy. The ABCB-1 mutation results in loss of function of p-glycoprotein, a protein responsible for pumping compounds out of the brain. The aim of this study was to determine whether differences in the ABCB-1 gene are associated with seizure control in canine epilepsy. Collies, a breed known to have a high incidence of mutation of the ABCB-1 gene, were studied. Epileptic dogs with the mutation were significantly more likely to have good seizure control and to be treated with fewer antiepileptic medications than epileptic dogs that were carriers of the mutation or that had the normal genotype. These findings suggest that p-glycoprotein may influence seizure severity in epileptic dogs. Further study is needed to determine whether this is a manifestation of the initial seizure disorder or reflects a response to treatment.

Recruiting Dogs for New Anticonvulsant Research
Julie Nettifee Osborne from North Carolina State University tells us that… a new anticonvulsant has been developed by a major veterinary pharmaceutical company.

“We are recruiting dogs that are not on any anticonvulsants at this time. Feel free to post the following link on your website, www.helpfordogswithseizures.com The study is nationwide and selection criteria and study information are listed on this link.

As for the Keppra study and the MDR study, they have both been completed, and we are in the process of writing up the results for presentation at the ACVIM forum in June. According to Dr. Munana, we should be able to share the results with them within the next few months, and would appreciate them posting the information on their website.

Other studies that are underway include a clinical study of Keppra Pharmacokinetics when given in combination with Phenobarbital. We actually still need a few dogs to participate that are on Phenobarbital at steady state levels, and Keppra. They do not have to come to NCSU-CVM, we can potentially arrange for sampling to be done and shipped to us from a referring DVM or Neurologist”...

We have received Dr. Ned Patterson’s current progress report on the research. Some exciting highlights are:

1. The two year grant that we provide financial support for and was due to end on March 30, 2010 will be extended an additional 6 months.

2. The researchers will analyze more Aussie samples using the new Illumina 150,000 – 200,000 SNP array. This new SNP array has just become available and has much more power than the previous SNP arrays.

3. Dr. Patterson is committed to continuing the search for markers and genes in Australian Shepherds as long as funds are available.

It is very important that we be ready to help provide the researchers with the funds necessary to enable them to continue this vital research to find the genes responsible for canine epilepsy and develop a screening test. We have assured Dr. Patterson that we are committed to continuing to raise funds and help collect blood samples for this important research and that we plan to increase our previous giving to support the research and do everything we can to assist him. We would like to at least double what we previously gave to support the research.

Dr. Patterson continues to work with Dr. Gary Johnson at the University of MO and Dr. Hannes Lohi in Helsinki, Finland. Dr. Patterson did have opportunity to meet with Prof. Lohi with an emphasis on the data in Aussies, ESS (and Vizslas). Their cooperative written agreement gives our Aussies and other breeds the best opportunity for a breakthrough and gives us the expertise and resources of each of these researchers.

Thank you for your help! We can’t do it without you!

Dr. Patterson at UMN, Dr. Johnson at UMO, and Dr. Lohi in Finland continue their efforts to find the genes responsible for canine epilepsy.

Dr. Patterson reports that additional Australian Shepherd cases and controls have been sent out for genotyping on the SNP arrays. “This new data will be combined with the previous data and the analysis will then be revised. Drs. Patterson and Lohi will coordinate a concerted effort to analyze more Aussies in the next 6 to 9 months. Dr. Johnson at UMO is also in the midst of sequencing some interesting genes in a few of the possible areas of interest for the Aussies.”

Dr. Patterson has also submitted additional ESS samples to his collaborators at the Mayo Clinic Shared Genotyping Resource. “Our hope is that one or more areas with an epilepsy gene of influence will now become more apparent.” Dr. Patterson recently had “a chance to talk in detail in person with Dr. Hannes Lohi about all the Epilepsy projects with an emphasis on ESS, Aussies (and Vizslas).”

“It has become increasingly apparent that IE is likely to be polygenic in most breeds. To date, to our knowledge, no IE gene has yet been identified in any breed. Our, now formal, agreement with the U of MO and Finland allows us to compare possible chromosomal areas across breeds - ESS and Aussie's (also Vizlsas and other breeds) in case there is a shared gene across breeds in which putting the data together might be more efficient in identifying the specific gene.”

There is now a formal written agreement for the sharing of Australian Shepherd and English Springer Spaniel DNA samples and data between Dr. Gary Johnson at University of MO, Dr. Hannes Lohi in Finland and Dr. Ned Patterson at the University of Minnesota . Dr. Patterson has done an outstanding job for us in working to coordinate this effort.

What this news means to us is that there are officially three researchers and institutions sharing data about our beloved Aussie and looking at it independently to insure that nothing is missed or overlooked. It is not too long ago that we did not even have one researcher with a grant to look at the Aussie and now we have three! Dr. Patterson writes that “all three institutions are separately analyzing all SNP data results in order to not miss any possible true areas containing an epilepsy gene(s)”. In addition the formal agreement will allow the researchers “to compare chromosomal areas across breeds – Aussie and ESS (also Vizlas and other breeds) in case there is a shared gene across breeds in which putting the data together might be more efficient in identifying the epilepsy gene.”

Dr. Patterson reports that there are 3 chromosomal areas of mild association from the initial data for the Australian Shepherd but since the association is only mild 50 additional Australian Shepherd samples will be run using the SNP chip. It is hoped that this will confirm or exclude these three areas and find other areas of possible epilepsy gene(s). There is also one area of interest for the English Springer Spaniel that has been observed but this association is only mild so additional ESS samples, cases and controls, will need to be analyzed.

Toby’s Foundation is dedicated to helping to stop one disease – Canine Epilepsy. This is a disease whose time has come… to be eliminated! We will be here until The Australian Shepherd gets a screening test and every other breed that needs one does too.

As we celebrate the 4th anniversary of Toby's Foundation, the timing and tools to find a gene marker for canine epilepsy have never been better! We are in a very good position with two outstanding researchers, Dr. Ned Patterson at the University of Minnesota and Dr. Hannes Lohi at the University of Helsinki, doing research on canine epilepsy in the Australian Shepherd to find the gene(s) responsible and develop a screening test.

Dr. Patterson and Dr. Lohi recently had the opportunity to meet for the first time in France in May. Dr. Patterson is coordinating with both Dr. Johnson and Dr. Lohi. In a progress report from Dr. Patterson, he said SNP Chip analysis has been completed on 30 affected and 30 unaffected Australian Shepherds by Dr. Hannes Lohi in Finland in collaboration with Dr. Gary Johnson at UMO-Columbia. Dr. Patterson at UMN is collaborating on statistical analysis of this data with them and is prepared to perform SNP chip genotypes and analysis on 20-30 additional affected and 20-30 additional unaffected Aussies in the next 6-9 months if significant association is not found and additional power is need for this breed. SNP markers are run by the Mayo Clinic in Rochester, MN who collaborate with Dr. Patterson.

AKC Canine Health Foundation Announced Funding for Epilepsy Study for the Australian Shepherd and the English Springer Spaniel

The AKC Canine Health Foundation announced "the United States Australian Shepherd Association, United States Australian Shepherd Foundation, Australian Shepherd Health and Genetics Institute, Toby’s Foundation and the English Springer Spaniel Field Trial Association Foundation all Partner to Contribute over $50,000 in Support." Click here to read the full press release.

We have added the Instructions information, the Dog Questionnaire and the Consent form for Dr. Patterson at the University of Minnesota . Dr. Patterson would like more samples from “affected dogs, and their unaffected relatives (2 generations any direction), and also some older (6 years or older) unaffected and unrelated dogs.” If you have already sent samples to Missouri , Dr. Patterson does have access to these samples. If you want to send a second sample to Dr. Patterson in Minnesota you can do so.

Among the things we learned at the Tufts conference focusing on canine epilepsy and bears repeating here are the more researchers looking at the problem the better and that ideally samples should be sent to all those who are working on canine epilepsy for the same breed. Please see our October 2007 research updates below in which we quote Dr. Patterson on this. If this is not possible you should at least send to one active study and CHIC. We have been recommending CHIC for all of 2007 (it was only set up in 2006). While CHIC is not per se a research study it is a very important repository to store samples for present and future use by researchers. By submitting samples to CHIC you insure that samples are there when needed for the future health of your dogs and your breed. Any researcher can apply to CHIC to use the samples and the samples can be used for any disease.

It is because we all did what was necessary to collect samples and raise funds that we were poised and ready and could in fact attract other researchers to take on the Australian Shepherd. Researchers need samples and funds for their work and the Aussie community was ready!

HARD WORK, PERSISTENCE and DEDICATION is PAYING OFF…WHAT A GIFT TO ALL OF US AT THIS CHRISTMAS and HOLIDAY SEASON

TOBY’S FOUNDATION, INC. is contributing ten thousand dollars ($10,000.00) to help fund a very important and equally promising Australian Shepherd Research Project to develop a screening genetic marker test for canine epilepsy in the Australian Shepherd breed. The grant is co-sponsored by ASHGI, USASA, USASF and the Canine Health Foundation (CHF) who will match each dollar that our organizations contribute to the CHF grant for Dr. Ned Patterson at the University of Minnesota. The grant is for SNP Association Mapping for Canine Epilepsy. “Dr. Ned Patterson (Principal Investigator) is an expert in the area of canine genetics and statistical analysis of pedigrees for heritable traits, and a clinician at the University of Minnesota Veterinary Medical Center. He will be responsible for the critical clinical diagnosis.”

Dr. Pamela C. Douglas, President of Toby’s Foundation said, “This is something we have been vigorously working on since first making the contact with Dr. Patterson at the Tufts conference in September 2007. We learned there that the more researchers working on the problem the better. Dr. Patterson told me that he had just been approved for a SNP Association mapping grant for the English Springer spaniel and perhaps could add Aussies to it if the Canine Health Foundation (CHF) agreed and the wonderful news now is they have agreed! Fortunately, we were poised and ready because we had all done our work in collecting samples and raising funds. This is truly a united effort by the entire Australian Shepherd community. I am so pleased and grateful for the support that we have received from everyone. I want to mention here the Aussie breeders and owners in Finland who with only about 1500 Aussies in their country were able to collect approximately 300 samples for Dr. Lohi even before he received the 64 samples from UMO. This is truly a dedicated breed that we are proud to be a part of.”

Dr. Patterson is an outstanding researcher who, as part of the consortium with UMO, has access to our Aussie samples. With SNPs now available to be used as genetic markers for mapping and two outstanding researchers, Dr. Patterson in Minnesota and Dr. Hannes Lohi in Finland working on the Australian Shepherd the time has never been better for this research. This is a two year grant. At this time we believe that more samples from affected dogs will be needed. We will let you know about this at a later time especially where and how to send them in.

“Of course it is always sobering," Pamela Douglas said, "to remember why we do this… to think about all the dogs that have been hurt and have succumbed to this disease and still will for some years to come even after a screening test is developed but at least the day will come when no more dogs and the people who love them will have to go through this.”

Dr Ned Patterson of the University of Minnesota College of Veterinary Medicine said at the Tufts Canine and Feline Breeding and Genetics conference “To help these studies progress we encourage individuals to submit DNA of purebred dogs affected with epilepsy and their relatives to the various studies. In the case where more than one group is studying the same breed I recommend individuals submit samples to all groups performing the studies”. Dr. Patterson said in notes from the Tufts Conference, "there are a number of ongoing projects trying to determine the gene or genes that cause IE (Idiopathic Epilepsy) in various dog breeds at the University of Minnesota, the University of Missouri - Columbia, the University of California - Davis, the University of Toronto, the Animal Health Trust in England, A University in Finland, and at a few other institutions." Click here to see Toby’s Foundation's recommendations for submitting your samples. The more researchers looking at the problem the better. Researchers can’t look at a breed without samples. They would have to rely on the one study that has the samples to share them with others. Toby’s Foundation will be putting out a list of research institutions that want samples for epilepsy research. We urge you to send samples from your dogs directly to 2 or 3 studies not just one.

We have been asked about CHIC. It is a repository not a study. CHIC has only been available for storage since 2006. It is a valuable resource that can ensure that samples are there for the future of your breed for research into many diseases including canine epilepsy. It certainly merits sending samples there.

We are in an exciting time now where several research institutions and studies either are or will be looking soon at canine epilepsy. We should support all the research that we can that is looking at the problem of canine epilepsy. This is a complex problem. The researchers were asked for their best estimate of how close we are to any breed getting the breakthrough. They said about 3-5 years unless we get lucky. Luck can happen and it recently did happen for the Aussie. Just ask Dr. Cathryn Mellersh who said at the Tufts conference that they got lucky…Mutation in HSF4 is associated with hereditary cataract in the Australian Shepherd.

Pamela:

I have attached some information that you may include on your website or in newsletters, but in short, we are recruiting for the following:

1. Collies, Shelties and Australian Shepherds for the MDR-1 study (click here for specifics). As long as pet owners are able to provide a copy of a recent anticonvulsant level that is in therapeutic range, we will send them brushes for MDR testing that will be performed at no cost to the owner. Results of the testing will be provided to each owner.

2. Dogs with Refractory Epilepsy (At least 4 seizures/month) are being recruited for an extension of the Keppra Drug study. Dogs for this study will have to travel to NCSU-CVM or the University of Tennessee approximately 7-8 times over a 44-week period.

For information regarding the above 2 studies, contact julie_osborne@ncsu.edu .

3. Blood samples from epileptic dogs are still being requested for a genetic study on canine epilepsy. For more information on this study contact carolinacanineepilepsy@gmail.com

Thanks for all you do to help out pets and their owners!

Warm Regards,
Julie Nettifee Osborne, RVT, BS
NCSU-CVM

November, 2006 - Toby's Foundation Completes Pledge for Research
Toby’s Foundation is pleased to announce completion of its $5,000.00 pledge. Thank you to everyone who helped us reach this goal. We will, of course, not stop here. We will continue to raise funds for the research to help stop canine epilepsy. The funds have been placed in a Donor Advised Fund for Aussie Epilepsy Research at the Canine Health Foundation and can be matched by them.

April, 2006 - For Immediate Release from Pam Douglas, President Toby's Foundation
As we approach the second anniversary of Toby’s Foundation, I have some very exciting news to share with you about the latest developments in the Aussie epilepsy research. We have gone from less than 100 blood samples just three years ago to over 1000 Aussie samples in the database as of April 2006 as reported at the USASA Nationals in MO! We have more samples in than any other breed! We are a committed group of Aussie breeders, fanciers and pet owners and the researchers have taken notice! The researchers have identified two Aussie family groups they can begin to work with. If we support the research now by filling in the missing links in family groups, raising the necessary funds for the Aussie research, submitting blood samples and if it turns out to be a simple recessive gene (which is how it now appears than the researchers), we may have a screening test in as little as 12-24 months. Otherwise, it will take longer. We have never been so close! As C.A. Sharp who attended the USASA Nationals said "We can see the light at the end of the tunnel!" We are very optimistic.

In addition, Toby’s Foundation has joined forces with the United States Australian Shepherd Foundation (USASF) and the Australian Shepherd Health and Genetics Institute (ASHGI) to raise $70,00.00 for Aussie epilepsy research. Toby’s Foundation pledged $5,000.00 to this joint effort. The funds will go to the Canine Health Foundation (CHF) and be placed in a donor advised fund (DAF) designated for Aussie epilepsy research. UMO is applying to CHF for grants and Erika Werne, Director of Canine Research and Education at CHF has told us that she will need the support of the Aussie community to raise some of the necessary funds to qualify for matching funds. Our $5,000.00 pledge will then become $10,000.00 as they match it dollar for dollar. Our joint ad with ASHGI and USASF will be out in the May/June 2006 issue of Aussie Times and the AS Journal.

October, 2005 - Pamela Douglas attended the ASCA Nationals.
We attended a seminar by Liz Hansen during nationals that gave an epilepsy research update. The good news—there are over 700 Aussies sampled as of October 2005! The bad news—there are a lot of “holes” in families.

92 of the samples are from affected dogs. Toby is one of the 92 affected dogs, but because of confidentiality, we don’t know the identity of the others.

We are asking the owners of the 92 affected dogs to join us in making sure that all of the dogs (both affected and unaffected siblings, parents, grandparents, and offspring) related to your dog submit a blood sample to the University of Missouri. It is very important that we have complete family information from all affected dogs and their relatives. Please do everything you can to get the samples submitted from all of your dog’s relatives.

Research Updates

Toby’s Foundation attended the 63rd Annual Meeting of the American Epilepsy Society