Research of Canine Diseases Helps to Advance Treatments & Understanding

Researchers studying canine diseases are helping to advance treatments that potentially will offer dogs a better prognosis. Here, we highlight research using stem-cell therapy to treat dogs with spinal cord injuries; two studies focusing on chronic active hepatitis (CAH); and research defining heat stress in brachycephalic breeds.

Stem-Cell Study Aids Spinal Cord Injuries

A three-year clinical trial at North Carolina State University College of Veterinary Medicine is evaluating stem-cell treatment options for dogs with spinal cord injuries. The participants are paraplegic dogs with Grade 5 injuries, which are considered the worst cases. These dogs have complete paralysis with a lack of sensation to their hind limbs. One participant in the study is a Cocker Spaniel mixed breed named "Tobi," who suffered from intervertebral disc disease (IVDD), a degenerative disc disorder. Owner Beverly Tucker of Thomasville, N.C., took Tobi to an emergency veterinary clinic when it was evident he had lost the use of his hind legs. Despite having surgery, Tobi still was unable to feel pain in his hind end, much less use his back legs.

"The veterinarian told us that if the surgery wasn't successful, it was likely Tobi would be paralyzed from the waist down," Tucker says.

Breeds that are genetically predisposed to IVDD develop Type 1 disease. These long-backed, short-legged dogs classically develop signs of IVDD from 4 to 6 years of age, although it can occur anytime from 2 years of age and older. Chondrodystrophoid breeds prone to IVDD are: Cocker Spaniel, Dachshund, Pekingese, Lhasa Apso, Shih Tzu, Basset Hound, Beagle, Poodle, and Pembroke and Cardigan Welsh Corgis.

In her efforts to help Tobi, Tucker learned about the clinical trial at North Carolina State University directed by Natasha Olby, VetMB, Ph.D., DACVIM, professor of neurology. The study is funded by the Morris Animal Foundation with support from the American Spaniel Foundation. There is no cost to participate, but owners must agree to transport their dog to the veterinary school for treatments and evaluations.

Olby's study, currently in the first year, involves evaluation of 30 paraplegic dogs following one of three treatments. She is recruiting 10 dogs a year. Five small-breed dogs, including Tobi, have been treated thus far.

The treatments are:

  • Injection of stem cells and Schwann cells into the spinal cord injury site coupled with an infusion of inosine, a substance with neuroprotective properties. The cells are suspended in an artificial cerebro­spinal fluid (CSF) that contains nutrients to help support the cells.
  • Inosine infusion only
  • Injection of artificial CSF only

Stem cells have the ability to rapidly multiply and to take on the function of specialized cells by assimilating various functions. Olby takes a sample of adipose, or fat, tissue and sensory nerves from the back of a dog's neck from which stem cells and Schwann cells are cultured. These adult fat-derived stem cells are cultured to produce neural stem cells. The Schwann cells produce myelin, a fatty substance that helps to insulate the nerves and allows them to conduct messages, in peripheral nerves. The therapy involves injecting the combination of stem cells and Schwann cells directly into the injured area in the spine.

Olby hopes to see improvement in the dogs that receive stem-cell therapy that will lead to a new treatment for paralyzed dogs. In order to benefit dogs, the therapy must generate new cells to do the work of damaged ones. After treatment, dogs are evaluated to assess changes in their ability.

"It's still early. We've only treated five dogs, and the scoring of their function will be done by blinded observers to allow objective assessment of the effectiveness of the treatments, but we are seeing promising results," Olby says.

Though Tobi still uses a cart to go outside and to stand up when eating, Tucker is pleased with the results of his treatment. "He can move his legs more and can push his feet forward a little," she says.

Owners of dogs with Grade 5 spinal cord injuries with complete paralysis are eligible to participate in the clinical trial. For information, please contact Olby at ivddstudy@lists.ncsu.edu.

Two Studies Focus on CAH

Owners of dogs diagnosed with chronic active hepatitis (CAH) commonly describe early signs of the disease — poor appetite, intermittent vomiting and lethargy — that could fit several disorders. Many times, owners do not learn their dog has CAH until the disease progresses to a severe condition.

While the prevalence of the disease in Poodles is not known, clinicians and genetic researchers are finding that Standards appear to be susceptible due to the disproportionate number brought to veterinary clinics for care. Believed to be a heritable condition, veterinarians caution breeders not to breed affected dogs.

"We're still in the infancy of evalu­ating this disease in Standard Poodles," says David Twedt, D.V.M., DACVIM, professor of small animal medicine at Colorado State University College of Veterinary Medicine. "We believe that Standards have a higher risk than Toy or Miniature Poodles and than other breeds. We just don't know what it is." Funding support from the Poodle Club of America Foundation is helping Twedt to characterize CAH in Standards, with a goal of developing an effective treatment. As Twedt and veterinary resident Allison Bradley, D.V.M., continue to collect tissue samples from affected dogs, they are optimistic they will learn more about the disease and what causes it. Chronic active hepatitis is ongoing inflammation of the liver that results in progressive damage to liver cells. Eventually scar tissue overtakes healthy liver tissue, leading to liver failure and death.

Based on their clinical studies, Twedt and Bradley speculate that some dogs with CAH respond well to immunosuppressant therapy, or medications that reduce inflammation or suppress the immune system. "We've had some preliminary success using cyclosporine to treat dogs with CAH," Twedt says. "It is an immune-suppressing drug that has been shown to stop the ongoing inflammation. Cyclo­sporine has an advantage over corticosteroids as it has fewer side effects, although a disadvantage is it is more expensive."

Stem-cell therapy may provide a future treatment alternative. Researchers at the Center for Regen­erative Medicine at Colorado State University already are experimenting with implanting new liver cells derived from stem cells in patients with liver disease or damage.

"We have harvested stem cells, and we're trying to make them into hepatocytes or hepatocyte precursors," explains Twedt. "Stem cells may actually generate new liver cells. They may also have an effect in decreasing inflammation. We are still quite a ways from clinical application in individual dogs."

Geneticist Mark Neff, Ph.D., director of the Program for Canine Health and Performance at the Van Andel Institute in Grand Rapids, Mich., is collecting DNA samples from all varieties of affected Poodles to study the inheritance pattern. The goal of identifying a linked marker potentially could lead to identification of the causative gene mutation.

Neff thinks Standard Poodles are likely to have a genetic predisposition to CAH based on breed predilection. "It is possible the gene has penetrated the adjacent gene pools of Toy and Miniature Poodles, despite the fact CAH is not commonly observed in these dogs," Neff says.

"With the modest cohort that we have, we're seeing what we refer to as 'trending toward significance,'" Neff says. "We haven't achieved statistical significance, but we're seeing a couple of regions in the genome that look like they are strong for the mutation. To learn whether there is a real positive association or to eliminate it as a false positive comes down to needing more samples. As few as 12 new cases could make a substantial difference in our findings."

For information about participating in Twedt and Bradley's research, please contact them at 970-297-5000 or by email at david.twedt@colostate.edu or allison.bradley@colostate.edu. For information about Neff's research, you may reach him by phone at 616-234-5000 or by email at mark.neff@vai.org.

Monitoring Brachycephlic Stress

Most breeders and owners of brachycephalic breeds are aware of the signs of respiratory distress and their breed's increased susceptibility to heat stress. Unlike dogs with conventional faces, brachycephalic breeds have shortened facial bones without the same proportionate shortening of the overlying soft tissues. The excess soft tissue makes them prone to upper airway obstruction that compromises their ability to take in air. Their inefficient panting and inability to cool down can result in inflamed, swollen airways that lead to a more severe obstruction and further overheating.

Recent research by Michael Davis, D.V.M., professor of physiological sciences and director of the Comparative Exercise Physiology Laboratory at Oklahoma State University in Stillwater, showed that a dog's body condition score has an even greater impact on thermoregulation, or the ability to maintain a steady body temperature, than does being a brachycephalic breed. The AKC Canine Health Foun­da­tion and several parent clubs helped to fund the research.

"Brachycephalic dogs are at greater risk for heat-related illness, presumably due to the structure of their respiratory tract," Davis explains. "Dogs rely on the respiratory tract to dissipate metabolic heat, and this process is hampered in brachycephalic breeds due to their airway anatomy."

The study confirmed that other factors should be considered as well. "While brachycephaly had an important impact on our research results, body condition score seemed to have a larger impact," Davis says. "In other words, being overweight is probably more risky than being brachycephalic and a lean brachycephalic dog may not have that much of a risk. The overweight brachycephalic dogs had two strikes against them."

While it is well-known that brachycephalic breeds are at risk of overheating during exercise and in warm climates, the parameters in which they are able to achieve homeo­stasis, or maintain physiological stability, have not been understood. Davis and his research team set out to identify those parameters.

Their study included 200 dogs — 100 brachycephalic dogs and 100 size-matched nonbrachycephalic dogs. Among the brachycephalic breeds were Boxers, Boston Terriers, English and French Bulldogs, Pugs, Japanese Chins, and Shih Tzu. Ten to 20 dogs of each breed were examined.

Using a whole-body plethysmograph, a custom-built box similar in size to a dog crate with rapid, sensitive pressure, temperature and humidity sensors, the researchers were able to detect and measure the impact of temperature and humidity changes on dogs by assessing their breathing patterns.

The heat stress levels used in the study were based on the maximum allowed by the U.S. Department of Agriculture (USDA) for dogs being transported by commercial airlines. The research showed that under mild heat stress conditions — 33 degrees Celcius (91.4 degrees Fahrenheit) and 62 percent relative humidity — the brachycephalic dogs were close to overheating. As the intensity of heat stress increased from a normal room temperature, defined as 22 degrees Celcius (71.6 degrees Fahrenheit) and 62 percent relative humidity, to mild heat stress conditions, the brachycephalic dogs overheated sooner than the nonbrachycephalic breeds.

"Only a few obese brachycepahlic dogs in our study could not handle the mild heat stress conditions, and they would be in jeopardy if they were transported under those conditions," Davis says. "More dogs would be in jeopardy if conditions managed to exceed USDA guidelines."

Most enthusiasts who are drawn to brachycephalic breeds realize it is important to take precautions against heat and humid conditions. Thanks to the research of Davis and his team at Oklahoma State University, more is known today about the parameters that define the risk of heat stress. Keeping brachycephalic dogs in ideal body condition goes a long way to help prevent respiratory problems.

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