Cardigan Health

Advances in Lymphoma Research

Reference Link

An interesting announcement supporting the One Health approach (animals and humans) to looking at disease. Hopefully this might translate into screening for our dogs to see who might be at risk for developing lymphoma.

COULD DOGS’ DNA GIVE CLUES TO HUMAN LYMPHOMA?

Scientists are rearranging the genetic information of certain dogs to make the coding human-like as a way to learn more about the genetic causes in people of non-Hodgkin’s lymphoma, a cancer that begins in the cells of the immune system. – (HealthDay, 4/12/2011). Reference Link Above 

Apparently there are some genes shared between human and canine lymphomas; the dog gene background is much less cluttered than the human one and is promising for future gene research. 

Also of interest (and great promise) in the same journal (Feb issue) is an article on a pilot study in dogs using a monoclonal antibody (mAb) therapy. The mAb binds to both normal and cancerous lymphocytes but only seems to induce suicide in cancerous cells. Very promising and early results indicate good safety. Now it appears to be headed to clinical trials. For those who have, have had or will have a dog with lymphoma, keep your fingers crossed as mAb therapy has been successful in some other cancers.

AKCCHF Study Report Regarding Canine Lymphoma

Posted November 14, 2013

In Fall 2012 the CWCCA donated $2500 from our AKC CHF account to help fund a study regarding Canine Lymphoma. During the course of the grant period, AKC CHF reports progress to supporting organizations. Below is the latest report.

Grant 01787: Clinical advancement of RNA-transfected CD40-B cell vaccine technology for cancer therapy

  Original Project Description: 

Canine lymphoma is the most common hematopoeitic cancer in dogs with an estimated annual incidence of 30/100,000. Chemotherapy induces remission in 75-85% of patients; however, the majority relapse with drug-resistant lymphoma within 8-10 months of diagnosis and most dogs die of their disease shortly thereafter. Cell-based vaccine strategies that stimulate anti-tumor immunity have shown promise in the treatment of many different cancer types including non- Hodgkin’s lymphoma (NHL) in humans. We have used a cell-based vaccine to induce antitumor immunity in dogs with NHL. This vaccine given three times after successful induction chemotherapy significantly prolonged overall survival. However, in the majority of dogs the vaccine did not prevent relapse but significantly prolonged second remission duration induced by rescue chemotherapy when compared to unvaccinated controls. These findings suggest that the lymphoma vaccine stimulated anti-tumor immunity but that this was insufficient to prevent relapse and only upon immunological boosting (through a poorly defined but previously recognized chemotherapy effect) could prolonged cancer free survival be realized. Here we aim to optimize our cell-based vaccine approach to induce functional, long lasting tumor-specific immune responses that aim to prevent relapse and prolong survival in dogs with NHL. This cellular vaccine will be generated in the presence of a potent immune stimulant and will be given every 2 months to dogs with NHL. The effects on tumor specific immunity will be evaluated. 

The goal is to optimize our vaccine/protocol to stimulate more effective anti-tumor immunity that will prevent relapse and prolong overall survival in dogs with NHL.

Report to Grant Sponsor from Investigator:

The goal of this proposal is to build on our previous work developing a cell-based vaccine that aims to stimulate potent tumor specific immune responses that will kill lymphoma cancer cells. Our previous work has shown that white blood cells known as B cells found in the peripheral blood can be activated and grown outside of the body using special “feeder cells” that express an important molecule known as CD40L. The stimulated B cells (known as CD40-B cells) can be loaded with genetic material (RNA) that has been extracted from the patient’s tumor. When re-injected back into the patient, the CD40-B cells are able to present the tumor material to the body’s immune system and stimulate an anti-tumor immune response. We have shown in a phase I clinical trial that this approach has produce promising results with respect to prolonging overall survival in dogs with lymphoma. We now aim to improve on this vaccine in two main areas; 1) we aim to improve the ease of vaccine production since our current methods are time consuming and require specialized laboratory equipment. This will enable us and other researchers with access to basic laboratory equipment to generate this vaccine and treat more patients, 2) we aim to improve the vaccine’s ability to stimulate anti-tumor immunity. 

Our current methods of generating the vaccine from lymphoma patients are labor-intensive and require specialized laboratory equipment that is not available in most facilities. Therefore, we are evaluating second-generation feeder cells that stably express CD40L (either the human or canine CD40L) as well as non cell-based techniques for canine B cell culture. Success in either of these areas will improve on our current process and ideally will enable vaccine production to occur in any basic laboratory without the need for expensive equipment. 

We are also testing the hypothesis that the vaccine’s ability to stimulate anti-tumor immunity could be improved by altering the culture conditions used to generate the canine B cells (ie. the vaccine), through the use of a potent immune adjuvant (CpG DNA). In the first 6 months of this work, we have made progress towards these goals. Our progress to date is summarized in the following bullet points:

1. We have employed more stable, second generation “feeder” cells that express human CD40L (KTCD40L) and have shown that these cells can activate canine B cells and cause them to proliferate in the same way as our first generation feeder cells. However, these second generation feeder cells are easier to grow and maintain in culture since they do not require antibiotic selection and are less sensitive to alterations in culture media acidity.
2.  We are in the final stages of generating a different stable “feeder” cell that expresses the canine form of CD40L, rather than our current human CD40L system, and in the next 6 months we will test the hypothesis that these canine CD40L expressing cells are superior to human CD40L expressing cells in generating canine B cells for cancer vaccines.
3. We have initiated experiments to evaluate a soluble form of CD40L that may be able to replace the requirement to use feeder cells for B cell culture altogether. If successful this would eliminate the need for a gamma irradiator (these are not readily available to many institutions and clinics) and for regular technical maintenance of feeder cell cultures.
4.  We have begun experiments to evaluate the effects of bacterial DNA, known as CpG, to our CD40L stimulated B cell cultures and our preliminary results suggest that CpG promotes the production of greater number of B cells and induces greater expression of B cell surface molecules that are necessary to stimulate anti-tumor immunity. These early results suggest that the addition of CpG to our B cell cultures may improve vaccine production and efficacy.

Together, this optimization work will direct the protocol we will use for a second generation B cell vaccine that will be utilized in our next CD40-B cell clinical trial. We aim to start recruitment for this trial in the Fall of 2013.

CWCCA Degenerative Myelopathy Study

Degenerative Myelopathy is a progressive neurological disease that affects many dog breeds including Cardigan Welsh Corgis. The purpose of this study is to determine definitive diagnoses of Cardigans with progressive spinal cord disease.

All dogs that develop DM will eventually become completely paralyzed and at this point there is no known treatment. In 2008, the University of Missouri developed a genetic test that can predict whether or not a dog is “at risk” for developing the disease. So far it appears that the incidence of this gene is relatively low in Cardigans. The most recent statistics from OFA state that of the 503 Cardigans tested, 50% are clear, 36% are carriers and 13% are at risk.

Not every dog that is “at risk” develops clinical DM and there are other neurological diseases like intervertebral disk disease that can be mistaken for it. DM can only be definitively confirmed by microscopic examination of spinal cord samples collected during a necropsy. Although there have been a number of suspected cases of DM in Cardigans, very few have been confirmed.

Please contact Barbara Merickel DVM, CardiganHealth@cardigancorgis.com if you have a dog that could be included. You and your veterinarian will need to complete a medical history/physical findings form. We will assist you in arranging for a necropsy (autopsy) which will need to be performed shortly after your dog had died or been euthanized. If you wish, your dog can be cremated with the ashes returned to you. The tissue samples will be sent to Dr. Joan Coates at the University of Missouri.

This study is open to all Cardigan Welsh Corgis, not limited to CWCCA Members.

Additional information and sample submission forms are available at http://www.caninegeneticdiseases.net/DM/mainDM.htm

Mizzou Study for the Treatment of DM

Published July, 2017

COLUMBIA, Mo. – In 2009, Joan Coates, a veterinary neurologist, along with other researchers at the University of Missouri and the Broad Institute at MIT/Harvard, found a genetic link between degenerative myelopathy (DM) in dogs and amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease in people. Now, MU researchers Coates and Michael Garcia, an associate professor in the Division of Biological Sciences, have found that a biomarker test that helps diagnose ALS also can assist with determining a diagnosis for degenerative myelopathy.

Coates is seeking clinical trial participants to evaluate a treatment for canine DM.

Coates is conducting clinical trial research for treatment of DM. The goals of the therapies being tested is to slow the progression of neurologic signs of DM and improve quality of life. These therapies are in collaborations with other ALS researchers and funded by the ALS Association and National Institutes of Health. The clinical trials are taking place at the MU Veterinary Health Center (VHC) Small Animal Hospital. To inquire about enrolling a dog, contact Coates at coatesj@missouri.edu.

Currently there are two ongoing treatment studies at the University of Missouri.  Below are the inclusion criteria.  Based on disease suspicion and early disease stage, the study may be able to pay for the MRI screening.  The diagnostic testing highlighted are to be done by the primary care veterinarian prior to referral to the University of Missouri because we need to make sure the dog is in good health.   

Both studies will be blinded with few dogs randomly assigned to a control group.  In other words, the study candidate has a 70-80% chance of getting the treatment.  Once the dog is selected as a candidate and assigned to a study, the specific details of the study will be thoroughly discussed.

Inclusion Criteria

History

Slowly progressive loss of coordination over 1-3 months, no signs of waxing or waning, and the owners do not perceive their dog to be in discomfort

Neurologic examination

EARLY DISEASE: Progressive asymmetric general proprioceptive ataxia that is considered mild. Breeds Included

• Boxers approximately 9 years of age or older at the time of initial examination
• Pembroke Welsh Corgis approximately > 10 years of age at the time of initial examination
• Other breeds older than age of 9 years old at the time of initial examination

Diagnostic Testing (Performed by a board-certified veterinary neurologist: www.acvim.org)

• No significant abnormalities on bloodwork, thoracic radiographs and abdominal ultrasound
• Genetic testing results for SOD1:c.118A mutant homozygotes (A/A – AT RISK)
• Normal entire spinal cord MRI (thoracic, lumbar, sacral)
• Normal CSF analysis
• Normal electrodiagnostic testing results

Treatments and Follow-up Testing

An informed consent will be signed by the owner and Dr. Coates. The owner must be compliant and return to the MU VHC as directed based on study protocol

Necropsy Confirmation

Following death or at time of euthanasia, the dog will need to be brought to MU VHC for necropsy.  A histopathologic confirmation of DM is required.

Together with the Genetics Committee of the ACVO, the OFA has recently completed the 7th Edition of “Ocular Disorders Presumed to be Inherited in Purebred Dogs,” commonly known as the Blue Book. The 7th Edition contains statistics through the end of 2014. The statistics represent all exam forms sent in by examining ACVO Ophthalmologists, regardless of whether the owners submitted the results for official certification. The statistics are grouped by years: 1991 – 1999, 2000 – 2009, 2010 – 2013, and the last year 2014 displayed by itself. The statistics prior to 2012 represent data previously collected by CERF. 

The text portion for each breed contains the breed specific Breeder Option or Ineligible for Certification conditions. These are in addition to those conditions which are considered Ineligible for all breeds including: Glaucoma, Keratoconjunctivitis Sicca, certain Cataracts, Len Luxation/Subluxation, PHPV/PHTV, Retinal Detachment, Retinal Atrophy, Retinal Dysplasia, Optic Nerve Coloboma, and Optic Nerve Hypoplasia. These pages represent the breed specific recommendations of the ACVO and are used by the OFA (and previously CERF) when issuing reports. 

Since implementing the eye registry at the end of 2012, the OFA has processed over 65,000 eye certifications, and an additional 50,000+ exam forms for the statistics. And in keeping with our non-profit mission “To improve the health and well-being of companion animals through a reduction in the incidence of genetic disease,” the OFA donates a portion of all eye registry revenues to the ACVO Vision for Animals Foundation (ACVO VFAF) that provides funding for grants in support of research into the elimination of ocular diseases causing vision loss and suffering in animals. In the last two and half years the quarterly donations to the ACVO VFAF have totaled nearly $70,000, so every OFA Eye Certification has a positive impact on canine health research! 

Eddie Dziuk
OFA Chief Operating Officer
2300 E Nifong Blvd.
Columbia, MO 65201
Phone: (573) 442-0418 x222, Email: edziuk@offa.org
OFA Website: www.offa.org

The dogs’ names listed in our database are a result of blood testing for the presence of the alpha subunit cGMP phosphodiesterase gene mutation known to cause Progressive Retinal Atrophy (PRA) in Cardigan Welsh Corgis. Dogs found to be unaffected/clear of the mutation do not pass it on to their offspring. The offspring of two unaffected/clear dogs should be unaffected/clear themselves. There were additional dogs posted to various computer lists and identified there as either carriers or clear/unaffected. However, because the results have not been verified, they are not included here.

This PRA Status Page is provided by the CWCCA as a service to breeders and puppy buyers. Breeders will find the list invaluable in identifying both PRA carriers and unaffected dogs in the pedigrees of their breeding stock. By identifying carriers and carefully selecting mates for these dogs, the eventual elimination of this disease is now possible. Puppy buyers can use this list to identify carriers in their puppy’s pedigree, also. However, be aware that the “Carrier” status of any individual dog does not affect that dog’s health in any way. It is the breeding of two carriers together that produces PRA. According to the American College of Veterinary Ophthalmologists, the Cardigan breed in North America has less than 1% of dogs affected with PRA.

To include a dog, please send either copies of the test results for tested dogs or pedigree information for line-cleared dogs to the PRA Database Administrator at:

Michele Neubauer
1002 Thorn Bush Road
La Grange KY 40031-8967

Contact:

Submitting PRA Samples

Optigen Testing
Cost of test: $80
Link to Optigen Site
Packaging & Shipping
Request Test (please note that online submissions save 5%)

Vetgen Testing
Canine PRA
Ordering Information (test is $80 with discounts offered for multiple samples):

VetNostic Testing
Canine PRA Test Cost: $65
Link to VetNostic Site