Cardigan Health: IVDD
The Cheree Kirkbride Memorial Grant for IVDD Research
Canine Intervertebral Disc Disease – IVDD
Although we do not have reliable statistics or risk factors, canine intervertebral disc disease is known to occur in the Cardigan Welsh Corgi. Studies show that there are likely many different factors involved, not the least of which is that the Cardigan is a dwarf (chondrodysplastic) breed and these breeds frequently suffer from Type I disk disease. Most studies of canine intervertebral disc disease have focused on the Dachshund, therefore that is the breed you will find most often referenced in the below links. Rather than reinvent the wheel when there is so much material out there, we present the following excellent links for your information:
We are proud to announce that the CWCCA has donated $5000 to the Texas A&M College of Veterinary Medicine Department of Neurology to help fund a project that will be analyzing the DNA of Dachshunds looking for genetic markers that predict the risk of developing intervertebral disk disease and to identify genetic factors that might correlate with recovery of spinal cord function. This project is a collaboration between the veterinary schools at Texas A&M and North Carolina State.
When we lost Cheree shortly after our 2015 National Specialty, her family asked that donations be made to the CWCCA Health and Research Fund in her memory. Like many of us, Cheree was very concerned about IVDD so we have been looking for a research project that would address its genetics in hopes that eventually we would have the ability to breed away from this devastating disease. The Health and Research Committee and your Board of Directors were so impressed with this project and the scientists involved that we decided to donate additional money from the Health Fund. If any of you would also like to make a donation:
1) By check – checks should be made payable to the Texas A&M Foundation and sent to the following address:
College of Veterinary Medicine
In the memo section of the check, please write “Neurology Fund”.
2) By credit card online – go to giving.tamu.edu and in the right hand corner, click on Give Now. Next, click on Veterinary Medicine on the left side of the page under College/Unit. As you complete the online form, please indicate under Designations that you are directing your gift to a specific account within the College of Veterinary Medicine. You will see a box appear and you will need to scroll down until you find Small Animal Clinical Sciences and click on Neurology Fund. After that, you may continue completing the form.
We would appreciate when making a donation if you would note that you are affiliated with the Cardigan Welsh Corgi Club of America.
If anyone has questions please contact me or Health and Research Committee members Campbell J. (Joe) Nairn, Vivian Moran or Lauren Simemeyer.
Barbara Merickel DVM, Health and Research Committee Chair
I. LAY ABSTRACT:
In the United States alone, there are 230,000 people living with spinal cord injury and associated health care costs range from $500,000 to $3 million per individual over a lifetime. There is currently no approved treatment for spinal cord injury, despite the fact that greater than 60 human clinical trials have been performed. These trials generally have used information from animals with experimentally-created injuries to identify molecules that might be targeted with a new drug. In this study, we propose to use Dachshund dogs with naturally occurring spinal cord injury as a means to identify genetic factors that might correlate with recovery of spinal cord function. These dogs develop spinal cord injury that results from acute rupture of the intervertebral disk, allowing material to rapidly compress structures in the vertebral canal. Injured animals may suffer from pain, paralysis, reduced quality of life, and even permanent neurological disabilities in a sequence that is very similar to humans. To date broad studies examining genetic factors that influence outcome in spinal cord injury have not been performed, despite speculation that these factors could be critical to the recovery process. Dogs are a logical choice for a genetic study because they have damage that is similar to humans, and because they are relatively in-bred which facilitates detecting genes associated with recovery from injury. Our goals are: 1) identify genetic variants associated with severity of spinal cord injury in the Dachshund; and, 2) to evaluate relationships between these variants and potential for recovery. The identification of genes that influence severity of injury or modulate recovery will have relevance to humans with spinal cord injuries: these genes might be used to refine prognosis of affected individuals and could identify new treatment targets. This project represents a unique collaboration between veterinarians, geneticists, and clinician-scientists at TIRR.
II. TECHNICAL ABSTRACT
Despite over 4 decades of research and >60 phase II and III human trials, no therapy has been shown to offer robust clinical improvement in people with spinal cord injury (SCI). The vast majority of human trials are based upon data from rodents with experimentally-induced SCI. While these models offer many advantages, they differ from human SCI with respect to the size of the spinal cord, immune responses following injury, post-injury treatment, and the spectrum of post-injury recovery.
We propose to use Dachshund dogs with naturally occurring SCI resulting from disk herniation as a tool for discovering genetic variants associated with injury severity and functional recovery; such variants have been speculated to modulate recovery in rodents, but as of yet have not been studied in any animal SCI platform. Dogs with disk-associated SCI are a promising model for human disease as SCI occurs in the un-anesthetized state in otherwise healthy young adults, results in analogous histopathology, can be stratified via validated gait and magnetic resonance imaging metrics, and is treated in a similar fashion to human SCI. Furthermore, dogs represent excellent models for identifying risk variants as the population structure, limited genetic heterogeneity and long linkage disequilibrium (LD) within breeds allow for genome-wide association studies (GWAS) to be performed using fewer numbers of individuals than would be required for a similar study in a population such as humans.1 Finally, Dachshunds have a lifetime incidence of disk-associated SCI that approaches 20% with >100 individuals admitted to our facility per year for this disease process. As such, the acquisition of large populations for future trials or discovery-based studies is feasible.
We have banked DNA from a large cohort of Dachshunds with SCI and varying degrees of locomotor recovery based on prospectively collected behavioral outcomes. We propose to perform a GWAS using a high density (1,200,000) canine SNP array in these cases to identify genomic loci associated with: 1) initial behavioral injury severity, and 2) long-term ambulatory recovery. Candidate genes will be identified within chromosomal regions associated with injury severity and recovery by querying the annotated online canine sequence assembly (http://genome.ucsc.edu/cgi-bin/hgGateway). These genes will be sequenced in a larger case cohort to identify variants that appear to modulate severity and/or recovery. The use of inbred, young and otherwise healthy dogs to perform this work greatly increases our chances of discovery, while genes identified as important in the injury/recovery pathways in dogs are extremely likely to be pertinent to humans. Genes and variants of interest can be investigated further both by stepping back to rodent models, and using genetic manipulation to perform mechanistic studies, and by using the knowledge to investigate the importance in people with a candidate gene approach This is a far more efficient approach than attempting to map people with extremely diverse genetic backgrounds, injury sources and complicating comorbidities. The ultimate goal of this project is to use a novel approach to identify clinically important pathways involved in injury/recovery and identifying genes that affect prognosis.
III. RESEARCH PLAN
a. Specific Aims
We hypothesize that genetic variation present in the Dachshund breed leads to susceptibility of intervertebral disk herniation (IVDH)-associated spinal cord injury (SCI) and further modulates the degree of functional locomotor recovery after injury.
The objective of this study is to perform a genome-wide association study using a high density SNP array to identify genomic loci, and potentially causal variants, associated with the severity and locomotor recovery in Dachshunds with SCI.
Results from this study may lead to the identification of genes and biological pathways associated with injury severity and recovery in humans with SCI.