Stem-Cell Therapy May Help Cats Resistant To Traditional Treatment For FCGS
A rescued domestic shorthaired cat named “Lily” has helped prove the efficacy of a game-changing treatment for feline chronic gingivostomatitis (FCGS), or stomatitis for short. The lucky feline, adopted by Cyndi Luke of Davis, California, had been treated unsuccessfully for three years when she was recruited to take part in a stem-cell therapy trial testing a cutting-edge procedure for the painful oral condition.
“Lily’s mouth was raw like razor blades had been raked over her gums,” Luke recalls. “She was down to 4 pounds, light as a feather. She’d run away from me, because I was the one always opening her mouth to give her medicine. It was so painful for her.”
After treatment with antibiotics, corticosteroids and painkillers, even having most of her teeth removed, Lily was not improving. Then, six years ago, the 12-year-old cat joined the first stem-cell clinical trial for FCGS.
Lily was one of seven cats in the study. None had responded to traditional treatment for FCGS. The trial, conducted at the University of California-Davis, involved extracting adult stem cells, or mesenchymal stem cells, from the cats’ own fat (adipose) tissue. The cells were cultured in a laboratory and then injected back into the cats. Five of the seven cats showed significant improvement.
“Lily seemed a little more comfortable after the first stem-cell transfusion, but her mouth still looked terrible,” Luke says. “After a second injection a month later, she was perky again and the lesions started going away. It was a miracle.”
Within a couple of weeks, Lily was off all her pain medications and eating normally. “It happened so fast,” says Luke. “This treatment definitely changed our lives.”
Thus far, the research team at UC Davis has treated 39 cats diagnosed with FCGS that were not helped previously by medications or extracting their teeth. After stem-cell therapy, a majority of those cats were cured or significantly improved, and the disease has not reoccurred in any cat that responded to the stem cells.
Impact of Stem Cells
FCGS is a severe, inflammatory oral disease that is extremely painful, causing many cats to stop eating. Traditional treatment includes medications and may involve surgically removing all teeth, yet only an estimated 30 percent of cats experience complete remission, 40 percent substantially improve and 30 percent are unchanged. The cats that do not respond to treatment need lifelong antibiotics as well as painkilling and immunosuppressive drugs. Cats that do not improve often are euthanized.
Cats with FCGS have red, swollen and ulcerated gums and mouth. Painful inflammation usually starts around an affected tooth, quickly progressing to nearby tissue until it affects the back of the mouth, the palatoglossal arch, and beneath the tongue. Lesions can develop on the lips, tongue, back of the throat, and roof of the mouth. Clinical signs include an inability to eat, loss of appetite and weight, withdrawn behavior, reduced grooming, excessive salivation, bloody saliva, bad breath, and pawing at the mouth.
Diagnosis requires a dental examination to evaluate the oral inflammation and ulceration as well as periodontal and gum disease. Blood tests and urinalysis can determine white blood cell count and concurrent diseases. Cats also may be tested for feline immunodeficiency (FIV), feline leukemia (FeLV), bartonella, or other viral infections.
All cats can develop stomatitis, but it occurs more commonly in those with compromised immune systems. “The incidence of FCGS is from 0.7 to 12 percent of cats, or from 500,000 to 11 million cats in the U.S.,” estimates Boaz Arzi, DVM, DAVDC, DEVDC, associate professor of surgical and radiation services at UC Davis. “I’ve seen more cases from multicat households.”
Although what causes FCGS is unclear, an inappropriate immune response is likely involved due to potentially multiple factors, including bacterial infections related to excessive plaque or periodontal disease, and viral infections such as calicivirus, herpes and feline immunodeficiency virus.
“With stomatitis, like other immune-mediated diseases, the immune system attacks the body’s own tissues,” explains Dori L. Borjesson, DVM, PhD, DACVP, professor of pathology, microbiology and immunology and director of the Veterinary Institute for Regenerative Cures at UC Davis.
“One thought is that a virus sets up a continuous loop of immune responses, triggering the response even after the virus is gone.”
Traditional treatments may not cure gingivostomatitis and can have significant side effects that diminish a cat’s quality of life. “These cats are suffering,” Dr. Arzi says. “This condition works well for stem-cell research because you can easily see if the treatment is effective by examining a cat’s mouth. You also can see when cats start gaining weight.”
The immune system of a cat with FCGS is essentially working on overdrive with little effect. “It’s like putting a car in neutral and pressing the gas,” compares Dr. Arzi. “But in a majority of cats, stem cells jump-start the immune system, which helps fight the disease.”
During the stem-cell culture process, the low number of stem cells found in the tissues is expanded to a higher number as they grow and divide. Ultimately, each cat receives 20 million stem cells per treatment. Other cells that are harvested, such as fat cells or endothelial cells, don’t survive the culture process. Thus, the stem cells that are returned to the patient are pure.
“Stem cells are administered to patients in a balanced saline fluid,” explains Dr. Borjesson. “We take low numbers of these cells that help heal tissues in a normal repair process and deliver high numbers back.”
In two consecutive studies, the UC Davis research team demonstrated that adult adipose-derived mesenchymal stem cells could be safely harvested, cultured in the laboratory and then injected into cats with FCGS. The studies are among four FCGS stem-cell therapy trials conducted at UC Davis that were funded by Winn Feline Foundation, a nonprofit organization that supports research devoted to feline health and medical problems.
All the cats had failed to improve previously from full dental extractions and immunosuppressive drugs. However, when they were given stem cells, up to 70 percent of the cats showed substantial or complete resolution of their disease. The success rate and response time varied depending on whether the MSCs were from the patient or a donor cat. Some cats still did not improve.
A new study has just begun at UC Davis testing stem-cell therapy in FCGS cats that have not yet had most or all of their teeth extracted. Because many cats with stomatitis also have periodontal disease that necessitates removing teeth, enrolling cats in the current study is challenging,
Dr. Arzi says. Finding an effective alternative to total tooth extraction will target early intervention.
“Of all the studies we’ve done, I think if we can show that stem cells can hold the disease without progression or improve cats’ condition without full-mouth extraction, this will have the biggest effect on the future of cats with gingivostomatitis,” he says.
The UC Davis stem-cell product is patented for use in oral inflammatory diseases in all species, including humans. It has been licensed to a veterinary stem-cell company that is seeking approval from the Food and Drug Administration to use the product to treat FCGS and potentially other inflammatory diseases in cats.
“The more you do, the more you learn,” Dr. Borjesson says. “We know more about stem cells and immune cells in cats than in any other veterinary species. Our area of biggest growth for stem-cell therapy is in inflammatory, immune-mediated diseases.”
Stem-Cell Advances
Adult stem cells, which come from mature tissue, are found in all body tissues but are generally harvested from bone marrow, placental and adipose tissue. MSCs have immune-modulating properties that reduce inflammation, though their primary job is to maintain and heal tissue. Thus, stem cells have become the focus of research into treatment of immune-related diseases, such as stomatitis and inflammatory bowel disease, as well as regenerative therapies to grow new bone, tissue and cartilage.
In cats, MSCs are more prevalent and easier to obtain from fat tissue than from bone marrow. Importantly, adipose MSCs are found in many parts of the body and can be injected from one cat to another without immune-system rejection. Mesenchymal stem cells that are removed from a cat then cultured and injected back into the same animal are autologous cells. Allogeneic cells are obtained from a donor cat, cultured and injected into another cat.
In their initial study, the UC Davis team used fresh, autologous cells, with 71 percent of the cats significantly improving or being cured in two to six months. Fresh, allogeneic cells were used in the second study, resulting in 57 percent efficacy within six to 20 months. As more data is collected, Dr. Arzi says, “the long-term success appears to be the same between the two types, but autologous is faster.”
Unfortunately, cats cannot always provide their own viable stem cells. The UC Davis team discovered that MSCs from approximately half the cats in the second clinical study could not be cultured because the cats had feline foamy virus (FFV). Relatively common, FFV does not harm cats or directly impact stomatitis or the efficacy of stem-cell treatments, but it does hinder the cultivation of stem cells.
As the research continues, Dr. Borjesson says they are beginning to test increased MSC dosages and to develop new allogeneic lines. “Our allogeneic work is progressing, and we are having many more successes,” he says. “Now we’re seeing more equality in the effectiveness of allogeneic and autologous stem cells.”
Also, the investigators say, fresh stem cells are more effective than frozen stem cell lines, which are commonly used in research because of their availability and convenience. Fresh MSCs take up to three days to cultivate but lead to fewer adverse reactions in cats that receive allogeneic stem-cell transfusions.
“Fresh cells are favored because we believe much of our efficacy data in cats with FCGS and in other ongoing clinical trials are related to the infusion of freshly expanded cells,” says Dr. Borjesson.
Another goal of the researchers is to study the mechanisms by which stem cells regulate immune-cell function. They hope to find biomarkers or cellular indicators that could help predict which cats are likely to respond to MSC therapy.
Blood taken from the FCGS study cats before treatment, for example, showed an overabundance of a killer subtype of immune system T cell, a cytotoxic cell called CD8+, which helps control viral infections. “In many of the cats that respond to MSC treatment, CD8+ numbers drop,” Dr. Borjesson says. “It’s too early to know how, but we think this is mostly a CD8-driven disease in cats and that CD8 cells are the ones destroying the oral tissues.”
There are various types of immune cells with different functions, and the levels of each one and ratio among them also may affect the disease and outcomes. “These may be signs of different causes of stomatitis,” Dr. Borjesson theorizes. “Perhaps some are not as responsive to stem-cell treatment. As a scientist, this is a new way to think about what’s causing this disease.”
“We don’t know what causes stomatitis, and we currently do not have an effective treatment,” Dr. Arzi reflects. “Research shows that stem cells are a viable alternative for cats when all else has failed. We hope it’s also a better and earlier treatment. Stem-cell technology is evolving so rapidly, someday we’ll be engineering stem cells to do exactly the job we want.”
Meanwhile, one of the main hopes of the UC Davis team is to have a better understanding of what defines the best conditions for using stem cells to treat FCGS. The ability to let clinicians know how to use stem cells, what to expect and how to get consistent results is the motive.
For cats like Lily, who is now 18 years old, it could mean a swifter, more effective treatment without the years of pain she experienced. “We are incredibly thankful for the stem-cell therapy that Lily had,” Luke says. “Just to see her feeling healthy again was the best part.”
Purina appreciates the support of the Winn Feline Foundation, and particularly Vicki L. Thayer, DVM, DABVP (feline), executive director, in helping to identify this topic for the Cat Update.
Winn Feline Funds Four Gingivostomatitis Clinical Trials at UC Davis
Winn Feline Foundation, a nonprofit organization that funds feline health research, has supported four stem-cell clinical trials at the University of California-Davis aimed at helping cats that do not respond to traditional treatment for feline chronic gingivostomatitis (FCGS).
“The impact of these studies has been tremendous,” says Vicki L. Thayer, DVM, DABVP (feline), executive director of Winn Feline. “Not only has this research benefited many cats with FCGS that are refractive to other treatments, it opens the door for broader application of stem-cell therapy in treating other oral conditions plus many more health problems.”
Here are the studies that Winn Feline has funded. Additional funding to support these studies has come from the National Institutes of Health and UC Davis.
- Autologous Adipose-Derived Mesenchymal Stem-Cell Therapy for Cats with Chronic, Nonresponsive Gingivostomatitis (2012-2014): Seven cats completed this clinical trial in which adipose-derived mesenchymal stem cells (adMSCs) were cultivated from their own fat tissue, then delivered in two intravenous transfusions four weeks apart. Five cats, or 71 percent, showed significant improvement or were cured within three to six months. Three cats experienced clinical remission. Two cats did not respond. This study was published in January 2016 in Stem Cell Translational Medicine.
- Allogeneic Adipose-Derived Mesenchymal Stem- Cell Therapy for Syncytial Foamy Virus-Positive Cats with Chronic, Nonresponsive Gingivostomatitis (2014-2016): Cats with FCGS that also tested positive for feline foamy virus, a common retrovirus that does not affect stomatitis but hinders the cultivation of adMSCs in many cats, were the focus of this study. Seven cats were treated with two intravenous injections of adMSCs cultured from donor cats. Fifty-seven percent responded successfully, with two cats showing significant improvement and two that were cured. Three did not respond. Overall, the response time was slower, taking up to 20 months. This research was published in August 2017 in Stem Cell Translational Medicine.
- A Multicenter Clinical Trial Using Autologous Adipose-Derived Mesenchymal Stem-Cell Therapy for Cats with Chronic, Nonresponsive Gingivostomatitis (2015-2018): The first part of this study has shown that fresh adMSCs could be shipped from UC Davis in California to Cornell University in Ithaca, New York, without losing purity or efficacy, provided the cells arrive within 24 hours of shipment. The second part of this multicenter trial is currently underway using donor stem cells to treat four cats each at UC Davis and Cornell, plus three cats at private practices in California.
- Early Intervention Using Autologous Adipose-Derived Mesenchymal Stem-Cell Therapy for Cats with Chronic Gingivostomatitis (2017-ongoing): The goal of this randomized, controlled and blinded study is to show that earlier treatment with a cat’s own stem cells is an alternative to costly and invasive, full-mouth tooth extraction. The researchers hope to enroll 10 cats in treatment or control groups. The treatment group will get two intravenous injections of adMSCs, administered one month apart. They expect adMSCs will reduce the oral inflammation and provide successful results equal to or exceeding total extraction. A second goal is to identify biomarkers that could potentially predict response to therapy and distinguish the 70 percent of cats that respond to adMSC therapy from the 30 percent that do not. Stem Cell Translational Medicine.
Cat Owners Can Help Advance FCGS Research
Research at the University of California-Davis is underway to learn whether stem-cell therapy can help cats diagnosed with feline chronic gingivostomatitis (FCGS) early in the disease process. Cats that have been diagnosed with FCGS and still have most of their teeth are eligible to participate. If more than 50 percent of the teeth have been extracted or need to be extracted, the cat will not qualify.
For information about participating, please contact Megan Loscar, RVT, or Dr. Boaz Arzi at 530-752-2470 or by email at dosclinicaltrials@ucdavis.edu.
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