Report to the DPCA Board of Directors
AKC Canine Health Foundation2011 National Parent Club Conference
St. Louis MOAugust 12-14
Marie-Alice Rousselle
Doberman Pinscher Club of Louisiana, Inc.
Copies of the Program, Presentation Abstracts, and Resource Reprints are enclosed with the hardcopy report and are available at www.akcchf.org/assets/files/2011-NPCCHC-Early-Release.pdfThis report will be based on my notes from presentations, hopefully to supplement the printed abstracts. I am a chemist, not a biochemist, so my perspective on the conference is that of a ‘civilian’ dog person, not someone with a background in molecular biology or medicine or vet medicine.
Before getting to the details of the presentations, I want to stress one theme that many speakers mentioned again and again – the great value of purebred dogs to medical research – notso much medical research using dogs as research animals, but especially the incredible advances that have been made based on studies and treatment of “owned” purebred dogs presented to vet schools. The breed-specific differences resulting from planned breeding have yielded breeds with significant genetic diversity between breeds, greatly facilitating genetic research that has also benefited human medicine. More than one speaker mentioned that many genetic discoveries would be extremely difficult if not impossible in random-bred dogs, i. e., mixed breeds (or indeed, in ‘random-bred’ humans!). This could be a valuable ‘talking point’ when defendingthe breeding of purebred dogs.
A second theme that recurred over and over is the value of ‘translational medicine’ – the cross benefits of canine research to human medicine, and of human research to canine medicine.
Friday August 12
Lee Arnold, CHF Board Chair, opened the conference and welcomed attendees. Terry Warren, CEO welcomed attendees and reminded us that 2011 is World Veterinary Year in celebration of the 250th anniversary of the profession of veterinary medicine. Steve Remspecher, Nestle Purina Pet Care, described the $10 million contributed by the Purina Parent Club Partnership Program since 2002 to support the Foundation’s operation and research.
Donald F. Smith,DVM, Cornell Univ.
HISTORY OF VETERINARY MEDICINE AND CANINE RESEARCH
Dr. Smith opened by discussing the contribution of canine research to human medicine, describing how animal studies led the way for transplantation of human organs, and the first ‘blue baby’ surgery.
He classifies vet medicine into 4 eras:
A) Early (urban) veterinary medicine.
In the Civil War, over 1 million horses and mules were lost to disease, starvation, trauma, inspiring more interest in veterinary medicine. With the dominance of horses and mules as the means of transportation in and between cities, vet med after the Civil War was an urban phenomena. Over 30 vet colleges opened in major cities in the latter half of the 19th century, including 5 in NYC and 2 in Chicago. Many were associated with medical schools.
B) Agricultural veterinary medicine.
With the development of the Land Grant Universities, and later the rise of cars as the prime means of transportation in cities in the early 20th century, vet medicine switched focus to the agricultural setting, dealing with animals raised as livestock. Vet schools now developed in rural locations, stressing admission of farm boys with a background in animal husbandry. Practice was primarily devoted to working animals and livestock, not pets. Surgical techniques developed in vet med were applied to human med. Aseptic surgical techniques were used in med schools on their colonies of research dogs long before they were applied in human medicine.
C) Development of specialties and increase in numbers of female vets
Following WorldWar II, a second-wave of land-grant vet colleges was opened, with a huge impact on research. Returning GI’s and their families acquired pets, leading to growth of vet med in urban settings again. Clinical specialties and board-certification began to become more common. With few vet colleges in urban settings, the Animal Medical Center in NYC and Angell Memorial Hospital in Boston became centers of vet med and research. Much research relevant to companion animals was based on private donations or piggy-backed on NIH-funded research using dogs as models for human disease. Later, access of female students to schools of vet medicine was enhanced, leading to larger numbers of female vets.
D) Genomic research
Recently purebred dogs have become the premier species for study of genetic basis of morphology, behavior, and disease. Developments in molecular biology and the determination of the human and canine genome have greatly advanced canine health research. But although over 80% of vets are involved in companion animal medicine, over 80% of gov-sponsored research is aimed at diseases of production and farm animals and public health, not companion animals.
Dr. Smith proposed the term “zooeyia” to refer to the physical, emotional, and psychological benefits of companion animals to humans and human health (the benefits of dog ownership on blood pressure and their owner’s exercise for instance, as well as service dogs, therapy dogs, ‘cell dogs,’ etc). Currently a significant proportion of funding of vet med research comes from an agricultural perspective, with little recognition of the value of companion animals to human health benefits in their owners. This could change with increased recognition of “zooeyia.”Dr. Smith sees the future of canine research as requiring a balanced approach, with funding coming from human medicine, foundation and private donations, corporate donations, and government funding of academic research. Currently only 0.5% of NIH grants are dedicated to vet med research.
Mark W Neff, PhD, Van Andel Research Institute
BEHAVIORAL GENETICS IN DOGS
Dr. Neff reminded us of the basis of genetic research in the studies of Darwin (the father of evolution) and Mendel (the father of genetics).The genetic diversity in purebred dogs permits studies of genetic control of features such as body plan and disease, and now the possibility of studying the genetics of behavior. Natural variation and artificial selection in reproduction both played a role in behaviors such as herding, drafting, chasing, etc. Behaviors such as herding or pointing are ‘hard-wired’ very early in the development of puppies, pointing to strong genetic influences. Natural variation permits study of how genes, their pathways, mutations, and genetic architecture work to produce variations in animal behaviors. Artificial selection by dog breeders for selected traits seeks to produce ‘large’ differences in behaviors, with an emphasis on ‘narrow’ characteristics of reaction, thus maximizing opportunities for research into the genetic basis of behavior. He described how the basic biology of instinctive behavior revealed by study of purebred dogs may be the key to understanding human mental illness and psychiatric disease.
Arleigh Reynolds, DVM, PhD, Nestle Purina PetCare
COPING WITH STRESS: NUTRITIONAL APPROACHES TO ENHANCE IMMUNE FUNCTION
Dr. Reynolds described how the mammalian immune system goes beyond white blood cells and disease-fighting, and includes the mucosal immune systems, including GI tract, respiratory system, and reproductive system. The gut for instance has 200X the surface area of the skin. He discussed his research studying stress such as experienced by dogs who travel and compete, using exercise as a model for stress with a colony of sled dogs he works with in Alaska, and using gut microflora to monitor immune response. He described how probiotics, antioxidants, and immunobiologics can improve a dog’s reaction to stress.
Among his findings:
‘dead’ probiotics can be beneficial, not just ‘live’ ones;
EBC (egg biologic compound) favored good gut microflora;
excessiveVit E and C can actually decrease the benefits of training, by decreasing production of endogenous antioxidants;
a product called “astaxthanthin” made from algea fed to salmon may be a significantly more beneficial antioxidant than Vit E/C
antioxidant supplements may be more beneficial during athletic competition than during training.
Albert Jergens, DVM. PhD, Iowa State Univ
ADVANCES IN DIAGNOSIS AND TREATMENT OF CANINE IBD
Dr. Jergens began by discussing progress and pitfalls in defining CIBD, e.g., how to differentiate IBD from food-related intestinal problems.Canine Inflammatory Bowel Disease is a chronic immune mediated disease. Diagnosis and establishment of severity and response to treatment, requires biomarkers for defining inflammation; clinical indices for defining severity; molecular diagnostics. There are problems with current histopathology standards and a need for novel therapies. Diagnosis requires exclusion of systemic disease, parasite-caused symptoms, food or antibiotic related symptoms, GI lymphoma, food sensitivity, and infectious diseases. There are breed predispositions in Yorkies, SCWT’s, Boxers, SharPeis, French Bulldogs, and Basenjis. Diagnosis must integrate signs, history, and tests. Tests that are used in diagnosis to rule out other causes include: gut biopsy, assay of cobalamin levels, ultrasound, x-rays, endoscopic biopsy, elimination diets, fecal exam.Interpretation of mucosalbiopsy results vary widely; studies support use of inflammation and morphologic features for defining inflammation. GI endoscopy is the ‘gold standard’ of diagnosis in CIBD, permitting observation of upper and lower bowl and testing of tissue samples. Mid-range gut cannot be easily biopsied with a GI endoscopy and usually requires an ‘open’ gut biopsy. GI endoscopy is preferred for ‘fragile’ patients. He described a CIBD Activity Index for evaluating severity, using attitude, appetite, vomiting, stool consistency, stool frequency, and weight loss. Work is being done looking at gene expression in CIBD, with evaluation by DNA microarrays and PCR to seek genes that are dysregulated in cell replication, immunity, mucosal defense, and inflammation in CIBD. 17 genes with maximal differences were looked at and correlated with clinical signs. The sicker the dog, the greater the number of gene perturbations. Patterns of gene expression were similar to human IBD, making the study of CIBD an excellent model for human IBD. Differences in gene expression associated with imbalance in microbiota were found. Clinical trials are planned to evaluate which parameters correlate to diagnoses, and drug trials will be conducted using clinical signs and biomarkers as measures of response. He mentioned that probiotics look promising.
Joan Coates, DVM, Univ of Mo
CANINE DEGENERATIVE MYELOPATHY: A TRANSLATIONAL MEDICINE APPROACH TO AMYOTROPHIC LATERAL SCLEROSIS – LOU GEHRIG’S DISEASE
Canine DM is an adult onset neurodegenerative disease, a progressive disease of the spinal cord. It is a non-specific description for a disorder of unknown causes; no sex preference; age of onset typically 8-14 years; typical duration of 6 mon – 3 yrs; typically 9-18 months to loss of ability to walk; a non-painful disease; breed predisposition in Boxers, some ChBayRet and GSD, Rhodesian Ridgebacks; DM has been diagnosed by histopathology in some 18 breeds. Initially, symptoms are those associated with upper motor neuron effects – weakness and ataxia in lower limbs, progressing to paralysis. If the dog survives long enough, lower motor neuron effects develop – weakness and ataxia in upper limbs leading to paralysis, general muscle atrophy, and difficulty swallowing and barking. Similarity to ALS has been demonstrated (ALS involves stiffness, slowing of movements, difficulty swallowing and speaking, muscle atrophy, and weakness), and Dr. Coates has a grant from the ALS Foundation. Ruling out other causes of the symptoms involves x-ray, myelography, CT, MRI, spinal fluid analysis. Histopathology shows lateral sclerosis, amyotrophy (changes in nerve fibers), and neuromuscular degeneration. In regards to genetic causes, breed tendencies and familial associations are found. SNP mapping of 38 DM dogs and 17 controls (mainly siblings) found an association with the SOD1 gene, a gene associated with Lou Gehrig’s disease.The mutation involves protein misfolding in relevant enzymes. A correlation between the identified gene and the DM phenotype has been demonstrated in several breeds. The mutation has been found in a large number of breeds. Since not all dogs develop DM, it is likely an incompletely penetrant autosomal recessive disease. Over 140 SOD1 mutations have been found in ALS; most of these mutations in humans are autosomal dominant. Dr. Coates warned of the significant dangers of trying to eliminate all DNA-affected or DNA-carrier dogs from breeding programs; this may cause severe breed bottle-neck or may increase other diseases. Genetic testing is available thru OFA. There no effective drug treatments; long-term prognosis is poor; physiotherapy may help. DM is the first spontaneous animal disease relevant to ALS. She has a NIH grant to evaluate use of ‘antisense oligionucleotide’ (sic) to shut down the SOD1 gene and to evaluate its safety and effectiveness in dogs.
Saturday, August 13
Jaime Modiano, VMD, PhD, Univ of Minnesota
RECENT PROGRESS IN MOLECULAR GENETICS OF CANCER AND CHALLENGES AHEAD
modiano@umneduwww.modianolab.org to subscribe to PDF newsletter
The website has the basics of ‘cancer 101.’ Dr. Modiano’s research interests include molecular diagnosis in cancers, molecular etiology of cancers,classification of tumors. Classification can be refined using tumor genotypes and molecular phenotypes. The role of heredity is unclear in 95% of cancer outcomes; it is a sporadic mutational event. The 1990’s saw the first use of DNA microarrays in studies of gene expression. In the last 10 yrs there have been many advances in application of molecular gene expression profiling to guide therapies. In the molecular classification by genome expression, there have been only<30 published studies in dogs. AKC CHF has supported 8 research projects in Dr. Modiano’s lab, resulting in a sample bank used by researchers worldwide. There are significant differences within tumors and among dog breeds, pointing to the dangers of generalizations.
For instance, in ‘recent’ European breeds, lymphoma is mainly B-cell, intermediate-grade, while in ‘older’ breeds it is mainly T-cell; are there benefits to classifying lymphoma when developing a therapy? Hemangiosarcoma- why is it the ‘tumor from hell’? Why does there seem to be a predisposition in GR’s? Osteosarcoma – can we predict who and how to treat?
In lymphoma, there are breed-specific differences in onset; it is rarer in Rotti’s, but with younger onset; it is more common in some other breeds, with older age of onset; there are genetic microarray differences between B cell and T cell and between high and low grades, with more difference in the T-cell lymphoma between high and low grades than in B-cell lymphoma. Low-grade T cell has a longer survival than high-grade T cell, but there is less difference in survival between high- and low-grade B cell lymphoma. PCR studies of gene expression has the potential to differentiate between B and T cell, and high and low grade. Molecular phenotype seems to be driven by ontongeny (sic) and cell origin, and less by heritable traits; may be ‘family relationships’ if not ‘breed relationships’. Clinical trials are now enrolling at U Minn to test a compound that may sensitize lymphoma-initializing cells to chemotherapy.
Hemangiosarcoma -some recent findings -there seems to be a distinct gene signal that defines HMS; research is looking for ‘cell signatures;’ there seems to be some gene-expression differences in GR’s as compared to other breeds. Prevention may require both genetic and non-genetic approaches. Mice that are genetically engineered to develop HMS can be injected with fluorescent markers, and the fluorescing HMS cells are proportional to tumor size, enabling detection of extent of disease. Sub-Q injection of HMS cells show that they migrate to spleen and other organs, and remain indefinitely with capacity to form new tumors. Changing the environment of a tumor, by for instance radiation or chemo, can change the tumor. Clinical trials are opening soon to evaluate treatment with targeted toxins.
Osteosarcoma – can we predict who and how to treat by genetic tests? Osteoblasts were isolated and grown out from 79 tumor samples. Two distinct groups were seen based on gene expression patterns; there were micro-environmental interaction differences. 2 different labs found a 2/3 – 1/3 spit. Branch A does poorly with treatment; Branch B does better. Breed influences the branching, but not survival. Gene expression patterns can predict who will benefit from treatment. Gene-based immunotherapy can improve outcomes.
Matthew Breen, PhD, CBiol, FSB, N State Univ SVM
COMPARATIVE CYTOGENETICS OF CANCER. JUST HOW HUMAN ARE OUR DOGS?
Dr. Breen’s research includes looking at how cytogenetics in cancer in dogs relates to humans. There are 80 million dogs in 40M households; approximately ¼ of dogs will develop cancer, the leading cause of death in dogs. The development of spontaneous cancers in dogs closely parallels human cancer. Clinical genomics attempts to improve identification of genes associated with cancer subgroups, characterizing the biological mechanisms underlying the association, and examining how genomics can improve treatments and outcomes. Human cancer has an occurrence rate of ~ 465/100K; in dogs, the rate is ~ 5300/100K, about 11x the rate in humans. This provides an opportunity to better understand cancer in dogs, and ultimately in humans. Correlation of tumor-specific chromosome aberrations with clinical outcomes has led to development of prognosis indications. The use of genomic date from 2 species can guide treatment in both species since humans and dogs have a shared pathogenesis of cancer. In vet med, “our dogs need help.” In human med = “our dogs can help us.” Cancer cells have a chaotic genome; when chromosomes go rouge, there can be wide differences. Human cytogenetic testing is widely available, notyet in dogs. Differences in meningioma(sic) was the first to be recognized by cytogenetic aberration, due to partial or total deletion of chromosome 22. Significant aberrations in dog chromosomes can narrow the search for aberrations in the human genome. For instance, in canine lymphoma, DNA aberrations include gains in 2 chromosomes (13 and 31) and deletion of 1 chromosome (14). Chromosome aberrations can distinguish between B-cell lymphoma and T-cell lymphoma. Such results can guide studies in humans. 744 cancer cases in dogs have been profiled. 4 subgroups were found by cytogenetic analysis. There were correlations of chromosome aberrations with diagnosis, subtype, andprognosis in dogs; such correlations should also be found in humans. This would be another example of ‘translational’ medicine, the transfer of knowledge from canine medicine to human medicine. Work has been done to develop a prognostic test to predict duration of response to chemotherapy in canine lymphoma. This involves ‘single locus probe’ analysis with multiple probes on lymphoma cells, to find variations in copies of the probes. Variations might include the existence of 3 copies or 1 copy instead of the normal 2 obtained from parents. Analysis is done of cells from dogs that held remission vs those that lost remission, looking for variation in copy numbers. In 121 cases, markers A and C differed. Marker A showed a significant ability to predict response to chemo. More copies of A & C may indicate a longer response of the dog to single-agent chemo with doxirubicin. In a study with lymphoma cells from 684 cases, copy # of marker A is significantly associated with duration of first remission with doxorubicin; copy # of marker C is significantly associated with response to CHOP chemo.
Nicola Mason, BvetMed, PhD, Univ of Penn
CANINE-DERIVED ANTIBODY FRAGMENTS FOR TARGETED THERAPY OF CANCER
In studies involving monoclonal antibodies, PCR is used to amplify ”single-chain variable fragment” antibodies (scFv antibodies) produced by B cells; libraries of scFv’s can be generated and chains of interest can be pulled out. The scFv’s can be cloned into phage vectors, generating libraries of scFv phages. Isolation and amplification of tumor-specific canine scFv’s can permit targeting antigen of interest. A ‘proof of concept’ study was done using canine parvo virus. After 4 stages of ‘panning’ the library, an antibody fragment that recognizes CPV was identified. The central hypothesis is that cancer patients will generate antibodies, and scFv phage libraries generated from canine cancer patients will contain antibody fragments against tumor antigens. For instance, VEGF is a potent angiogenesis factor in tumor growth, survival, andmetastasis; it is expressed in many different tumor types. Research looked for fragments recognizing VEGF in hemangiosarcomain dogs and evaluation of scFv’s that are VEGF-specific for neutralization of VEGF bioactivities. After 5 or 6 rounds of ‘panning.’ scFv’s specific for VEGF were obtained. These scFv’s yielded 3 clones that inhibited angiogenesis activity of VEGF. The fragments will be tested by injection into mice HAS cells for effect on HAS ell growth, looking for a theraputic effect in mice. This will be followed by canine trials.Sc’s can be produced in bacteria, which is significantlycheaper that production by mammalian cell culture.
Douglas H. Thamm, VMD DACVIM, Colo State Univ Animal Cancer Center
CANINE ONCOLOGY TRIALS
Canine cancer clinical trials are conducted to find better means of diagnosing, treating, and monitoring cancer in dogs (and humans). Sometimes, clinical trials are the only financial option for dog owners. There are advantages in the use of pets as models: they present with natural spontaneous disease; dogs are outbreed compared to rodents typically used in medical research, but are relatively inbred compared to humans; dogs have a favorable body size; the canine genome has been published, with >500 SNP markers; the canine genome is closer to the human genome that the rodent genome is; the biochemistry of dogs is more similar to humans than rodent biochemistry; the canine organ-specific blood flow is more similar to humans than is the rodent. Taking osteosarcoma in canines and humans as an example: common sites, x-ray presentation, cytology, clinical outcomes; cost of clinical trials in dogs is less than for humans; canines are a less heavily pre-treated when joining the trials; there is better compliance and more necropsy compliance in canine trials; faster progression of disease = shorter data turn-around. Clinical trials include trials of new modes of treatment, prevention (meds, vaccines, vitamins, lifestyle (i.e., smoking in humans), diagnostics, screening, and also quality-of-life improvement. Phase 1 trials are for ‘dose-finding’ and toxicity determination: what is a safe dose; what are side effects; what is the toxic dose. These are typically short-term, looking at pharmakinetics, target modulation (what is bio-effective dose), anti-tumor effect. At this stage, an anti-tumor effect is secondary to the other goals, but researchers still want to see an effect on the tumor. Phase 1 cancer clinical trials are usually single-agent, but can include combo agents later. They typically are “3+3” – 3 patients at a low dose; 3 patients at an increased dose; 3 more patients at a further increased dose, until dose-initiated toxicity occurs. An ‘accelerated’ trial might involve 1 patient/dose until mild toxicity is seen. Phase 2trials usually have 15-25 patients @ a dose level determined in phase 1 trials. The primary goal is anti-tumor response with toxicity and dose response as a secondary goal. Results are described as: CR = complete response. PR = partial response, >50% reduction in tumor volume or >30% decrease in diameter. SD = stable disease state. Lack of response = >20-25% increase in volume or diameter. ORR = overall response rate of subjects. PFI = progression-free interval. OS = overall survival. Phase 3 trials are randomized, comparing ‘new’ treatment with the current ‘standard of care’ or comparing ‘standard of care’ to ‘standard of care + a new drug.’ Response, PFI, and OS are important endpoints at this stage. These trials will typically be carried out at several locations. When considering enrolling a dog in a clinical trial, owners will be considering: what is current standard of care (and its cost & effectiveness); what are the alternatives to an unaffordable standard of care; what is known about the treatment being studied and its toxicity? The “Nuremberg code” for human trials requires: informed consent; risk/benefit ratio must be highly beneficial; investigators must have adequate skills. Studies @ academic centers are usually supervised by an Institutional Animal Care and Use Committee and a Clinical Review Board. Pet owners can look for similar requirements in canine trials. Clinical trials can be found at a site managed by the Veterinary Cancer Society at http://www.vetcancersociety.org/clinical-research.html
Rondo P. Middleton, PhD, Nestle Purina Research
VITAMIN D AND CANCER
Vitamin D was originally identified as necessary for metabolism of calcium and phosphate and proper bone mineral absorption. For instance, in the late 1800’s, the ‘English disease; (rickets) was found to be related to low exposure to sunlight due to either low levels of sunshine or high levels of air pollution. Around the turn of the 20th century, vitamins (‘vital amines’) were discovered, and the role of Vit C in prevention of scurvy was identified. Vitamins A and B were next discovered, and in the early 1920’s Vit D was discovered, followed by discovery of Vit D2 and Vit D3. In the 1960’s and 70’s, the metabolically active forms of vit D were identified as 2,5dihydroxyVit D and 1,25 dihydroxyVit D. The metabolic route from Vit D to Vit D2 and then Vit D3 and the role of uv sunlight exposure in their metabolism from dehydrochlosterol in the skin was identified. Sunlight exposure doesn’t increase Vit D in dogs; they need to get it from food. Vit D3 (calcitriol) plays a role in cancer, heart disease, autoimmune diseases, and skin disorders, among others. Later research found Vit D (esp the hormonally active form , 1,25-dihydroxyvitain D3, ‘calcitriol’) plays a role in cancer, cardiovascular disease, diabetes, auto-immune disorders, and the immune system, via the vit D receptor (VDR). VDR binds to specific regions of DNA and regulates the expression of vit D responsive genes. The discovery that VDR is found in many tissues not involving calcium homeostasis led to the discovery of other roles of calcitriol. In cancer, Vit D3 metabolic enzymes are altered. Dr. Middleton’s research has studied how calcitriol effects gene-expression changes in canine cancer, and the apparently beneficial role of antioxidant enzymes in cancer cells.
Karen Greenwood, BSc., Pfizer Animal Health
FACTORS INFLUENCING DEVELOPMENT OF NEW VETERINARY MEDICINE ONCOLOGY PRODUCTS
The search is on for new vet med therapies for canine cancer. Oncology research can be an example of ‘translational medicine’ whereby human medical research benefits dogs, since target pathways may be the same, leading to an opportunity to better understand cancer in both species. Cancer is estimated to occur in 1-2.5% of dogs; some 4.2 million dogs a year are diagnosed with cancer. Off-label use of human products has been necessary, but the products are not optimized for use in dogs. And in dogs, there is a need to avoid side effects that would be acceptable to save the life of a human patient. Recent discoveries of new oncology products include Pfizer’s Palladia for treatment of mast cell tumors. It is the first canine small-molecule oncology product to be launched. Merial’sOncept is a new melanoma vaccine, the first and only USDA-approved therapeutic vaccine for treatment of cancer (in either animals or humans). Development of new products required identifying a target first. The target must be essential to the tumor, yet not be too important in healthy tissue. It may be selected from canine med literature, or from human med literature, which requires cross-testing in dogs to see if the target is also in dogs. It may also be selected from basic research using tumor samples. The next step is identifying a compound. It may be a compound used in human med, or a relative of such a compound. It may come from libraries of compounds screened for activity against cancer. It may be a potential cell-surface antigen against which monoclonal antibodies or vaccines can be directed. 1) Evaluation of a compound against a target first involves confirmation in vitro. The use of 1536-well plates facilitates has facilitated such confirmation by high-thru-put screening involving receptors, enzymes, or ion channels. 2)The next step is confirming confidence in the results – compounds or antibodies of interested are tested in cells from real tumors or in mice with canine tumors (resulting from xenografts). 3) Dosing regime and safety must be established; what will route of administration be; does compound last long enough in dogs to impact the tumor; is the compound safe (‘safe enough’) in rodents and healthy dogs? 4) The compound is then tested in canine patients. Does it modulate the target; is the intended pathway impacted? Only then can the compound move on to a phase 1 clinical trial. Manufacturing factors are considered. How expensive? Can drug be made consistently? Is there a good shelf life? Development studies must be done to prove efficacy and safety in large (~100) patients with the disease. Regulatory pathways include FDA’s CVM for pharmacological products and some antibodies; USDA for vaccines and some antibodies; EPC for pesticides and anti-parasite products. The Animal Med Drug Use Clarification Act of 1994 allowed off-label use of human meds in dogs. A product that is found to be safe, effective, and able to be manufactured must then compete with potentially cheaper off-label use of human drugs and must be beneficial when compared to current ‘standard of care.’ New compounds must show efficacy as ‘single agents’ even if they will not be used only as single agents. The Minor Use –Minor Species (MU-MS) process offer route to develop compounds for rare diseases or uncommon species. “Minor use” in dogs is defined as <70 cases in dogs/yr. Compounds launched for major species can be used in minor species. Compounds for ‘minor use’ can be as costly to develop as products for major use. Marketing of new products requires specialized colleagues to share the information and guide use of new product. Adoption of new therapies is influenced by: regulatory situation, cost of development,incidence of disease, willingness of owners to use therapy., willingness of vets to try new approach. As to the future for canine-specific oncology treatments, many tumors are not common enough; lymphoma is common and agents developed to treat it may be effective in other tumors, old human drugs will continue to be valuable, new human drugs will probably be cost-prohibitive for use in dogs. Opportunities include vaccine or biological treatments for common tumors, increased incentive for MU-MS treatments, translational medicine will be an important pathway to i.d. and develop new agents.
PANEL DISCUSSIOIN – FUTURE OF CANINE CANCER RESEARCH AND TREATMENT
Duane Butherus, PhD, moderator, and the presenters of papers on canine cancer
Subjects discussed in response to audience questions included: $50 billion a year spent on human med research vs $2 million a year for canine med research. Human med needs to recognize they can get ‘big bang for the buck spent’ in canine med. What is future for use of Vit D? Vit D can be overdosed in canines and humans, but most research supports increasing RDA; calcitriol has benefits but can have serious side effects. Use of calcitriol with chemo has benefits. What is role of environmental pollution in cancer? Tobacco and sunlight are most significant exposures in humans; there is a tendency to over-emphasize role of pollution in cancer. Is incidence of cancer in dogs higher than in humans? This may be true for common cancers in dogs. Is there an association of viral causes in lymphoma and HAS? Retroviruses in dogs may have had enough time to evolve to be more benign in dogs than in humans, but we don’t have good evidence for role so far. Other comments: We cannot yet make breeding decisions based on cancers such as lymphoma. There are human drugs available from manufacturers to vets for use in pets because they are at or close to expiration date, while still being effective. This can decrease cost of therapy.
The Vet Cancer Society has a website to assist in location of clinical trials:
www.vcancersociety.org
The CHF has a section on finding opportunities to participate in tissue sample recruiting and clinical trials:
www.akcchf.org
Susan LaCroixHamil, CHF Director & AKC Delegates Health Committee
PARENT CLUB HEALTH INFORMATION AND THE AKC BREEDER OF MERIT PROGRAM
The BOM program includes a certification that applicable health screenings as recommended by the Parent Club are done on breeding stock. AKC looks at requirements from a club’s Code of Ethics, CHIC requirements, website info, a parent club’s Membership Application, AKC breed flyers, etc., etc. There is great variation from breed to breed in where and how recommended health screenings are delineated. Ideally, parent clubs should define requirements for BOM program, specify where the requirements are posted, see that they are easily accessible, ensure that they are verifiable, see that they are clearly stated, encourage participation by members, and communicate with their members on the BOM program. The Code of Ethics may not be the best site for identifying health requirements for BOM. CHIC may be more flexible.
AKC would like to see the parent clubs ‘raise the bar’ for the health component of BOM. Requirements should be meaningful but attainable, and should be flexible as priorities shift or new tests are developed. AKC wants to work in cooperation with parent clubs to further develop the BOM program.
Kathryn M. Meurs, DVM, PhD, North Carolina State Univ. CVM
WHAT WE KNOW ABOUT THE INHERITANCE OF DILATED CARDIOMYOPATHY, ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY AND SUBAORTIC STENOSIS IN THE DOG
Dr. Meurs defined an inherited heart disease as one that a dog is genetically programmed to develop; the disease can either be congenital or adult-onset. Some inherited heart diseases may befamilial, but not develop until later in life. A familial heart disease may not be the same disease in different breeds.
DCM: Phenotype: It is most commonly found in Doberman Pinschers in the US. It is a heart muscle disease of adult onset, typically>5 years of age. In addition to Doberman Pinschers, it can be found in Great Danes, Irish Wolfhounds, Scottish Deerhounds, and Newfoundlands – large breeds that Dr. Meursdescribed as requiring’ two hands to pick up.’ DCM is not the same disease in all these breeds. Likely due to a different gene in the different breeds. In Doberman Pinschers, it has an autosomal dominant mode of inheritance (a dog with 1 bad gene may show disease) but with highly variable penetrance. In the Great Dane, in some families it is carried on the X chromosome; females can be silent carriers. DCM Molecular aspects: In humans, >20 different genes can cause DSM. In studies of 48 affected and 48 unaffected dogs, looking at 50K SNP’s, a 16-base pair deletion was found in Doberman Pinscher DCM. The deletion means that less heart muscle protein is produced; the deletion decreases RNA expression in affected dogs. The cardiac mitochondria are abnormal because the heart muscle is not getting enough energy. Since>20 genes are involved in human DCM, it is likely that >1 gene is involved in DP DCM. In Dobermans, some die of heart failure, some die of ‘sudden death.’ Penetrance: In humans,penetrance is relatively low and is age related; maybe 20-30% of those with ‘bad gene’ will show disease. The mechanism of variable penetrance is poorly understood. Could it be related to diet? To exercise?To luck? It is not possible to predict penetrance; we can know who has the mutation, but not who will develop the disease.
ARVCM: This form of heart disease is most common in Boxers. The heart muscle looks ‘moth-eaten’; there is a disruption of electrical signals; leads to sudden death. It is autosomal dominant with variable penetrance, age-related variable penetrance. In homozygous dogs, there are more abnormal heartbeats. With ~ 72% penetrance, ~ 72% of dogs with the mutation will show disease.
There are DNA tests for Doberman DCM and Boxer ARVCM. A negative test does not mean the dog can never get the disease; it just means they won’t get the disease from this mutation. A positive heterozygous dog is at increased risk, but not absolutely certain to be affected. The strategy should be to always breed a homozygous or heterozygous dog to a negative dog, then select for quality in pups to replace the parent with a clear dog. Ideally, a positive homozygous dog should not be bred, but in the case of a significantly superior specimen, it might be necessary to breed, breeding the dog to a negative and ultimately selecting for clear dogs of high breed quality. Removal of all dogs bearing the mutation from a breeding program is NOT recommended; the DNA data must be used to guide breeding, with the goal of eventually increasing the population of clear high quality specimens. The DNA information should be used in conjunction with phenotype testing.
I asked if there is any chance of getting a better handle on penetrance. Dr. Meurs said penetrance is not fully understood in humans,so it is not likely to be understood any better in dogs. Because the disease is mitrochondria-related, diet and exercise may play a role in development of active disease in carriers. I thanked Dr. Meurs on behalf of DPCA for her research on DCM.
Cynthia M. Otto, DVM, PhD., Univ of Penn, Penn Vet Working Dog Center
SEPTEMBER 11 – TEN YEARS LATER FOR THE SEARCH AND RESCUE DOGS
SAR dogs working the 9/11 site had no ‘personal protective equipment’ as recommended for humans. Data on dogs who worked the site were examined to look for acute problems and long-term problems. Some 300 dogs were deployed. In deployed dogs, the median age was 5 yrs, with a median training time of 5 years; 11 breeds were involved – 31 GSD, 28 Labs, 12 Goldens. Dogs worked at the World Trade Center, the Pentagon, and at the landfill to assist in location of human remains. One factor that may be significant is that all dogs arrived post-collapse of the Towers, meaning they were not exposed to the clouds of debris-laden air in the immediate aftermath of the collapse. 10 years later, 96 of 300 deployed dogs had died.
In looking at acute problems, based on handler surveys the most common were cuts and scrapes, in 35% of the dogs. Respiratory problems were negligible. No eye problems were reported, probably because of intervention (washing of eyes). 65% of the dogs experienced fatigue, with a higher incidence in males than females. 8 dogs showed respiratory distress; 5 of those worked the WTC site. The keys to acute health maintenance seems to be: work/rest cycles; adequate nutrition and hydration; eye flushes (very important); proper training to prevent injury in rubble, and adequate monitoring during deployment.
Long-term effects involved medical and behavioral surveillance and annual testing (primary vet checks, CBC and blood chemistry, chest x-ray, survey, and serum toxicology screening. Long term effects were studied in the 96 dogs deployed at the WTC, the Pentagon, or the landfill, with comparison with 55 non-deployed dogs who were on average ~ 1yr younger than deployed dogs. In the first year after deployment, higher immunoglobulin, bilirubin, and alkaline phosphatase were seen; these resolved by 2 years post-deployment. Toxicology screens found no measureable toxins in the blood; no lead, mercury, etc. Chest x-rays showed minimal pulmonary changes and some heart changes (small size changes, some evidence of DCM.
Outcomes: 75 of the 96 dogs who were deceased 10 years later had an average age at death of 12.5 years. 33 of 55 control dogs who were deceased had an average age at death of 11.8. There were no differences in rate of death related to which site the dogs worked. Most common cause of death was cancer, 40% in deployed and 45% in control dogs. Types of cancer were: HSA: 9% in deployed, 9% in controls; Lymphoma: 4% in deployed, % in controls; Lung: 3% in deployed, 6% in controls; adrenal: 3% in deployed, 9% in controls. Long term, there was no difference in frequency of medical or surgical problems.
Dr. Otto said if you wanted to speculate on what might have contributed to the health maintenance of the deployed dogs, you might conclude that ‘long noses are better filters’ than human noses. Dogs don’t smoke or drink. The dogs were not there at the collapse. Dogs don’t get asthma. It might be the ‘needle in the haystack’ – looking at only 96 deceased dogs is a small statistical sample.
Other findings: In terms of the human-animal bond, SAR handlers were found to be highly resilent, with less PTSD than other responders working at the sites. However, when a SAR dog dies, the handler becomes more vulnerable.
One legacy of 9/11 is the Penn Vet Working Dog Center, focusing on detection dogs, esp SAR dogs, looking at health and fitness, genetics/epigenetics, training, performance standards. Studies can provide educational resources for vets and vet students and working dog handlers. They are working on a new building and working with breeders on breeding, recruiting, and training for SAR dogs. They are hoping to develop a working dog medical facility and create community programs such as puppy-raising. Breeders can help by breeding detection dogs and providing DNA from successful detection dogs. They would like to develop a National Detection Dog Electronic Medical Record that can follow a working dog from site to site as it is deployed and encourage studies of canine health related to performance. On the 10th anniversary of 9/11, a Working Dog Conference will be held 9/7 – 9/9.
Sunday August 14
Christine Haakenson, PhD, AKC CHF
CHF & GRANT SPONSORS – WORKING TOGETHER FOR A HEALTHIER WORLD FOR DOGS
The goals of the AKC CHF include funding of canine health research, ensuring scientific soundness of funded research, dissemination of information back to clubs and breeders. The club CHF Health Liaisons are vital links between the Foundation and breeders. The CHF benefits from the support of AKC, corporate sponsors such as Purina & Pfizer, Parent Clubs, OFA, and breed health foundations. The CHF funds research on genetics, epidemiology,improved methods of treatment, diagnosis and prognosis determination, molecular biology. The process involves first identifying problems, with input from breed clubs. Once applications for funding of research are submitted, CHF oversees internal and external reviews leading to grant approvals, and then monitors research progress. Benefits of the CHF oversight include rigorous reviews, identification of researchers, grant management (only 8% overhead costs are allowed on CHF grants, compared to 25+% in many grants), project monitoring, sponsor collaborations, progress summaries, and sponsor acknowledgements. Parent club inputs include identifying of breed health concerns and sharing of ideas. The CHF health liaisons are the primary contact for health and research communications, participate in educational programs, provide breed-specific health concerms, communicate and share knowledge with parent club members, receive oproject updates, and receive sponsor reports and Donor Advised Funds statements.
Health Liaison Communications include:
Late Jan – DAF statements & individualized sponsorship opportunities
Early Apr – Purina Parent Club Participation funds are received
Late Jul – DAF statements and sponsorship opportunities
Late Oct – announcements of new “oak” projects to begin in January(“oak” projects are major projects)
Late Feb/Aug – grant progress summaries
Oak grants – 1st report due in 6 mon; Acorn grants – lst report due in 1 yr.
Health Liaison e-newsletters are issued in mid-Feb, mid-Mar, mid-Aug, mid-Nov.
Club health committees can contact CHF for sponsor opportunities throughout the yar as needed.
Available reports include: Progress summaries, DAF info, grant sponsor reports. Sponsor opportunity reports. A Health Liaison Handbook will be available. Additional resources are available with a newly revised website.
Educational outreach by CHF includes:
Breeder symposia: 11/5 @ UnivMinn, 9/6 @ Tufts breeder & Genetics Conf.
National CHF Parent Club Conference
Newsletters
On-line canine health info including podcasts, videos, research success stories, canine health info.
BREAKOUT SESSIONS – three breakout sessions were held. I tried to select three that would be relevant to DPCA members.
DEVELOPMENT AND USE OF CANINE HEALTH SURVEYS
Robin Nutall, OFA
Robin Nutall has been with OFA since 1996 and has been working on the surveys for 3+ years.
OFA health surveys are done to determine the incidence ofgenetic diseases in a breed.
Surveys cover both registered and non-registered dogs, since in most breeds <50% of dogs are registered, and the surveys seek to develop health data on as many purebred dogs as possible.
OFA works with a breed club to develop a survey specific to that breed. Surveys are done on-line; parent club can request hardcopy.Incidence surveys – has a dog been diagnosed with specific diseases included in the survey. This leads to screens specific for adisease. Surveys are completely confidential, with absolutely no record or tracking of participants. Since they are online, surveys are easily accessible. Survey is done for each owned dog. Time range covered in a survey is determined by the parent club, as is the duration of availability of survey online. The parent club determines whether a survey is open or closed. Parent club can ask thata survey allowfor updates. OFA works with a parent cub to develop a survey with maximum input from the club. OFA recommends that a survey be as comprehensive as possible in diseases covered, to reduce the incidence of ‘other’ answers. Sample surveys are available, including one in Word format. A club can begin with a ‘pilot’ survey and later expand it based on initial results. Written sample surveys are available.
GENETIC TESTS: HOW TO INTERPRET RESULTS AND INCORPORATE THEM INTO YOUR BREEDING PROGRAM
Jerold Bell, DVM, Tufts SVM
Dr. Bell will provide permission to clubs to reprint the resource papers on this topic (beginning on page2 38 and 42 in Resources section of program) for non-commercial purposes). Request permission from jerold.bell@tufts.edu Any reprints must include the phrase “appears with permission of the author.
(My note: these are excellent papers, and DPCA should consider reprinting them or putting them on the website.)
“Genetic tests” include not just DNA-based tests, but can include phenotype, linked-marker, or mutation-based tests. Genetic tests can/should at least put ‘selective pressure’ into breeding programs. Just as characteristics defined by a beed standard are selected for, genetic health should be selected for. Genetic health should put ‘selective pressure’ on every generation. In some diseases, such as degenerative myelopathy in Wire=haired Fox Terriers, 91% carry the gene, but there are 0% affected – there is no penetrance. When there is a high frequency of a mutation in a breed with no overt disease, there is probably an effect of a ‘susceptibility’ gene. Genetic tests should not limit breeding choices, but should guide breeding choices. Breeders should not eliminate all affecteds. Genetic tests do not decide which dogs to breed, but which dogs to breed them to. These thoughts are more fully developed in the two resource papers mentioned above. My question – What role can phenotype (such as longevity) play in complex situations such as Doberman Pinscher DCM? Dr. Bell said parameters such as longevity could be a benefit in older-onset severe conditions such as DCM, but it still goes back to DNA testing.
Eddie Dziuk, OFA
CANINE HEALTH INFORMATION CENTER (CHIC) AND DNA REPOSITORY
Mr. Dziuk referred us to papers in the Resources section of the program, pages 50-57.
He said the breakout session would cover questions raised by the group. OFA has a staff of 12; 2 deal with CHIC.
How are breed requirements decided? A parent club health chair brings proposed requirements for a breed. CHIC and the parent club discuss the requirements, with approval from the parent club. The club then appoints a CHIC liaison to receive quarterly reports. CHIC incorporates historical data from OFA into the initial database.
When a club adds new tests, do previous dogs remain in CHIC?
Periodic adjustments to requirements are allowed, and previous dogs are grandfathered in.
Additional OFA results that are not required will be included if already in the DNA database.
What is the process if a DNA test is available, but a dog is not tested and declared ‘clear by parentage?’
“Clear by parentage” is allowed only for a direct DNA gene test, not for a ‘marker-linked’ test. A “CBP” is issued only for the first generation, not subsequent generations. Sire, dam, and offspring must be DNA-profiled to establish unquestioned parentage. The CHIC # will have a “CBP.”
CHIC #’s should not be used as ‘approval for breeding.’ It’s not about ‘normalcy.’ It’s about encouraging testing and openness.
CHIC DNA Repository – co-sponsored by OFA & CHF.
It is a central bank where DNA is available to the research community. It is voluntary and semi-open.
DNA may be from cheek swabs or blood samples. Univ of Mo receives and processes all blood samples. UC Davis receives and stores all swab samples. BLOOD SAMPLES ARE MUCH PREFERRED, AS IT PROVIDES MORE DNA. Swab DNA doesn’t provide enough for use with SNP microarrays. So if a club plans a DNA clinic, go for blood samples. Cost is $20/sample. OFA may underwrite 50% of the cost. This is not a volume discount, but underwriting by OFA. OFA banks DNA from known affecteds for free.
Availability of DA from the Repository means that researchers don’t have to include cost of processing in a grant. They can just get stored DNA.
Comments:
If DNA is banked from a dog that later develops a disease, how is that updated?
The parent club needs to remind members to update data in such a situation.
There is no way for owners to access database, so owners can’t update deaths or diagnoses.
Question: Could owners have access to a form to submit such updates to CHIC?
Not all researchers know of the DNA bank. CHF needs to let grant recipients know of DNA bank where relevant.
If a researcher requires DNA and has a grant from CHF, NIH, MAF, then DNA will be provided.
If researcher is not funded by CHF, IH, or MAF, requests will be handled on a case-by-case basis.
5-10 cc of whole blood will supply researchers for years, depending on quality and quantity of blood. It should provide samples to >5 researchers.
February 2nd, 2012 | Category: 