Summer 2014

Heal Thyself

Stem cell therapy holds promise for treating many incurable diseases in pets and people

By Genevieve Rajewski

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Illustration: Stuart Bradford

“Oh my god, come look at Bella,” Diane Joseffy heard her husband call out. “She’s actually sitting down!”

Joseffy’s yellow Labrador retriever Bella hasn’t sat willingly in years and not for lack of obedience training. The 11-year-old dog suffers from anal furunculosis, a painful condition that causes foul-smelling skin lesions in tissues in and around the dog’s rump.

“It’s a horrible disease, and one without a certain cure,” says Claire Sharp, a veterinarian at Cummings School of Veterinary Medicine at Tufts. She and other veterinarians at the school’s Foster Hospital for Small Animals are looking at stem cells—those multipurpose cells that have the potential to become many types of tissue in the body—as a new way to treat the condition. “It’s especially sad because the dogs have a really compromised quality of life, even though the rest of their body is totally healthy,” Sharp says. “We really don’t know what triggers the disease, but we suspect it has an autoimmune cause.” Some research suggests that normal intestinal bacteria may provoke the body to attack itself and destroy healthy tissue.

Joseffy tried to control Bella’s disease for seven years with two immunosuppressant drugs that cost about $500 a month. When her husband lost his job, she asked her veterinarian whether there was a cheaper way to treat her pet. She got lucky. When her veterinarian consulted with Lluis Ferrer, a veterinary dermatologist at Cummings School, she was not only advised on how to switch to one immunosuppressant, she also learned about the school’s free clinical trial, which is assessing whether stem cells, paired with conventional medications, can cure or improve anal furunculosis.

Joseffy and Bella were in.

Biological Repair Kits

Stem cell therapy is considered by many to be the most important breakthrough in the life sciences since genetic engineering. Researchers in human medicine are exploring the use of these cells to regenerate cardiac tissue in patients with heart failure and brain tissue in stroke patients, for example. Because stem cells send out signals that regulate immune system function, they also hold great promise as biological repair kits for diseases in which the immune system is out of whack, as in lupus or multiple sclerosis; chronic inflammation (rheumatoid arthritis); or dangerous scar tissue, such as the kind that develops after some heart attacks. At Tufts School of Dental Medicine and Tufts Medical Center, scientists are looking to mine these cells’ potential to treat chronic dental pain and the nonhealing foot ulcers common in diabetics.

The FDA has outlawed the sale of stem cells for use in human medicine, and any stem cell treatment must meet the same standards as a traditional drug trial. With the exception of bone-marrow transplants—which have been used since the late 1960s to replace diseased blood-making cells with healthy ones—stem cell therapy has not been approved for human patients in the U.S.

Because stem cells send out signals that regulate immune system function, they also hold great promise as biological repair kits for diseases in which the immune system is out of whack.

At Cummings School, stem cell research is focusing on several canine diseases for which traditional treatments often fail. The work could speed the development of stem cell therapies for humans with similarly difficult diseases.

“We are gravitating toward patients that are pretty dire,” says Andrew Hoffman, director of the school’s Regenerative Medicine Laboratory. Funded by a $1 million grant from the Shipley Foundation, Cummings School veterinarians will test stem cell therapy on such canine conditions as spinal-cord injuries that have caused paralysis, fatal kidney disease and an inflammatory disease of the brain and nervous system that’s akin to multiple sclerosis in humans.

The hope for these clinical trials at the Foster Hospital, Hoffman says, is that the participating dogs will be able to live more comfortably or, better yet, be cured. The veterinary researchers also will determine whether stem cell therapies can improve patient outcomes in other ways, such as reducing the cost of long hospital stays associated with a chronic disease or lengthening the time between relapses.

Cummings School veterinarians chose anal furunculosis for one of their first clinical trials, in part because it’s similar to a complication seen in some people with Crohn’s disease, an inflammatory bowel condition affecting as many as 700,000 individuals in the U.S.

Drugs that suppress the immune system combined with a high-fiber diet have helped some dogs, and people, recover from perianal lesions. For others, this treatment provides only temporary relief. In some dogs and people, these conditions become debilitating.

Given the high rate of relapse for Crohn’s patients, researchers have begun to investigate whether stem cells could help. In a study published in February in Gut, the journal of the British Society of Gastroenterology, researchers reported that stem cells successfully treated lesions in seven Crohn’s patients and shrank lesions in three other cases—all without any adverse effects.

Bella was in the first group of dogs to participate in a similar clinical trial at the Foster Hospital. For the study, Sharp drew bone marrow samples from Bella and four German shepherds; none of them had responded to conventional therapy. Hoffman used these samples to grow large numbers of mesenchymal stem cells in the lab. Ferrer, the veterinary dermatologist, then injected those cells into and around the lesions once a month for three months.

The dogs experienced no ill effects, and four of them had a 30- to 70-percent reduction in the width, length and depth of their lesions. (The owner of one dog with extreme lesions decided to euthanize it before the study ended.) Ferrer presented the results of the study in April at the North American Veterinary Dermatology Forum.

“Bella’s lesions didn’t go away,” notes Joseffy, “but they seem a bit improved. She has been doing better on just one medication since the stem-cell injections.”

In a follow-up study, Ferrer and Sharp will evaluate whether using mesenchymal stem cells derived from human embryonic stem cells will produce better outcomes than treating the dogs with their own stem cells. Because the potency of the stem cells may vary greatly from dog to dog, using stem cells developed from a more uniform source will allow veterinarians to better evaluate the therapy’s effectiveness. “It can be difficult to tell if a treatment works when we are essentially giving all the patients a different pill,” Hoffman notes.

One Medicine

Another clinical trial at the Foster Hospital will look at the effectiveness of stem cells in treating dogs whose intestines rupture after they have eaten a sharp object.

As the intestine leaks into the abdominal cavity, the gut’s naturally occurring bacteria cause a severe abdominal infection known as sepsis. Forty percent of these dogs will never leave the hospital, despite aggressive treatment that involves surgery and high doses of antibiotics.

“It’s not the bacteria in their bellies that kill these dogs so much as the animals’ immune response to the bacteria,” says Sharp. As the revved-up immune system attacks the onslaught of bacteria, it can cause life-threatening collateral damage to the body’s blood-making abilities, kidney, liver and lungs.

If the stem cells function as expected, Sharp says, they should keep the immune system in check and prevent the infection from taking over.

Like dogs, people whose intestines rupture are at high risk of dying, even when they receive the best care. “Abdominal sepsis in people is a huge area of interest in medical research,” says Sharp. “But those clinical trials take years to develop and still more years to see results. They also cost billions and often fail,” says Sharp.

“We have an opportunity in veterinary medicine to get an idea into clinical trials much more affordably,” Sharp says. Each stem-cell pilot study at Cummings School costs about $5,000 per dog; a similar human trial would run $20,000 to $100,000 per patient, depending on the study.

Unlike in rodent studies, in which drugs often appear to work but later in fail in human patients, “we do all the same things to save dogs with abdominal sepsis that are done in human medicine,” says Sharp. “So if we see benefit in our patients, that should be an extra impetus to consider the treatment in humans.”

To bolster the application of veterinary research to human medicine, Cummings School has filed several stem-cell pilot studies with the FDA Center for Veterinary Medicine. This creates an important public record of the steps involved in the harvesting, growth, storage and delivery of stem cells to patients.

“We have an opportunity in veterinary medicine to get an idea into clinical trials much more affordably.” —Claire Sharp

The FDA also collects the research plan, or protocol, for each clinical trial. Designed to safeguard the health of participants and answer questions about experimental treatments, the protocol outlines the reason for conducting the study; the schedule of tests, procedures and stem-cell injections and dosages; and what information will be gathered about the participating animals, among other data. Most important, the FDA makes suggestions about how to conduct the trial better, including how to improve the client-consent forms so that pet owners are absolutely clear about the benefits and risks of participating in a clinical trial.

Collectively, such research protocols will create a national resource about which stem cells work best for which diseases and how well the canine disease models predict the success of such treatments in humans.

Because dogs are so anatomically and physiologically similar to humans and live among us—therefore sharing our environmental risk factors for disease—Hoffman expects that the results in dogs will be highly predictive of how humans with similar medical conditions might respond. But, he says, the possibility of finding new therapies for canine disease alone is payback enough.

“These pets desperately need alternatives,” says Hoffman “They need help just like people do, and we have to start somewhere.”

Genevieve Rajewski, the editor of this magazine, can be reached at genevieve.rajewski@tufts.edu.

To learn more about clinical trials at Cummings School, visit go.tufts.edu/vettrials.

 

A FIELD GUIDE TO STEM CELLS

There are several kinds of stem cells, and each plays a different role in the body.

Embryonic stem cells (also known as pluripotent stem cells) are the most clever and versatile of all the stem cells because they can develop into anything a body needs: kidneys, eyes, heart, teeth, you name it. They can be isolated five days after a sperm fertilizes an egg.

As an embryo develops into a fully formed animal, these stem cells essentially choose a career path and lock into it. For example, embryonic cells will make kidney cells that will forever remain kidney cells, heart cells that will always be heart cells and so on. A core population created by the embryonic stem cells is known as adult (aka somatic) stem cells.

Every organ in the body contains highly specialized adult stem cells that may be activated in response to tissue damage. Heart stem cells may go into action after a heart attack, for example. The majority of adult stem cells fall into these six categories:

Field Guide_graphic_300px1. Neural stem cells generate several types of specialized cells in the brain and spinal cord as well as cells outside the central nervous system that communicate with one another to produce physical sensation, cognition and vital functions, such as breathing.

2. Endothelial stem cells replenish blood vessel and lymphatic cells, which are the building blocks of the intertwined circulatory and immune systems.

3. Found in the lining of the digestive tract, skin, lungs and other specialized organs, epithelial stem cells produce several kinds of cells that exchange fluids or nutrients with their environment.

4. Mesenchymal stem cells can generate bone, cartilage, fat and other kinds of connective tissue. Easily harvested from bone marrow, fat or umbilical cord tissue, these cells are often used in clinical trials in human and veterinary medicine.

5. Reproductive stem cells replenish eggs or sperm in the body, helping to maintain fertility.

6. Found in bone marrow, hematopoietic stem cells generate the body’s red and white blood cells, which live only about four months before needing to be replaced.

 

FOLLOW THE EVIDENCE

Even though veterinary stem cell science is in its nascent stages, several companies are already marketing veterinary stem cell therapies, most often for treating arthritis or soft-tissue injuries. They manufacture kits for veterinarians to harvest bone marrow or fat from an animal and mail those samples back to the company. The firms isolate the stem cells and return them to the veterinarian, who injects them into the animal.

Dog_x300Michael Kowaleski, V93, an orthopedic surgeon who is conducting clinical trials of stem cells for treating elbow osteoarthritis in dogs at Cummings School’s Foster Hospital for Small Animals, says pet owners should proceed with such treatments only if there are proven, evidence-based results. Unlike in human medicine—in which sales of stem cells are banned and stem-cell treatments must undergo the same approval process as a drug—neither the FDA nor the U.S. Department of Agriculture has regulations governing the sale and use of stem cells in veterinary medicine.

Before agreeing to stem cell therapy, Kowaleski recommends that pet owners ask their veterinarian these questions:

      Why are you recommending this approach?
      How does it compare with other treatments that are available?
      What is the evidence for the safety of this treatment?
      Was the treatment effective, and what were the objective measures for determining that? For example, in an arthritic animal, were tests done with a force plate to show that the animal was able to bear more weight after the treatment, or were the results determined by owners’ observations that the animals seemed better?
      Was the research peer-reviewed, meaning was it determined to be valid by experts in the field who were not associated with the study?
      Was there a control group of animals that received a placebo, such as a saline injection, and how much benefit did the stem-cell treatment produce compared with the placebo?
        Was the research “blind”? That is, were the owners and researchers prevented from knowing which animals received the treatment and which ones received the placebo to ensure that expectations did not influence the results?
        Who funded the research, and does a commercial concern stand to benefit from it?

 

 

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