AT Update CA NESTLÉ PURINA PUBLICATION DEDICATED TO ENTHUSIASTS VOLUME 16 | SUMMER 2018

STEM-CELL THERAPY Helping with Unresponsive FCGS SUMMER 2018 STEM-CELL THERAPY MAY HELP CATS RESISTANT TO TRADITIONAL TREATMENT FOR FCGS

A rescued domestic shorthaired cat Lily was one of seven cats in the named “Lily” has helped prove the study. None had responded to tradi- efficacy of a game-changing treat- tional treatment for FCGS. The trial, ment for feline chronic gingivosto- conducted at the University of matitis (FCGS), or stomatitis for California-Davis, involved extracting short. The lucky feline, adopted by adult stem cells, or mesenchymal Cyndi Luke of Davis, California, had stem cells, from the cats’ own fat been treated unsuccessfully for (adipose) tissue. The cells were three years when she was recruited cultured in a laboratory and then to take part in a stem-cell therapy injected back into the cats. Five of trial testing a cutting-edge proce- the seven cats showed significant dure for the painful oral condition. improvement. “Lily’s mouth was raw like “Lily’s mouth was raw like razor “Lily seemed a little more com- razor blades had been raked blades had been raked over her fortable after the first stem-cell gums,” Luke recalls. “She was down transfusion, but her mouth still over her gums. She was to 4 pounds, light as a feather. She’d looked terrible,” Luke says. “After run away from me, because I was a second injection a month later, down to 4 pounds, light as the one always opening her mouth she was perky again and the lesions a feather.” to give her medicine. It was so started going away. It was a miracle.” painful for her.” Within a couple of weeks, Lily

Cyndi Luke, the owner of a domestic After treatment with antibiotics, was off all her pain medications shorthaired cat diagnosed with feline corticosteroids and painkillers, even and eating normally. “It happened chronic gingivostomatitis having most of her teeth removed, so fast,” says Luke. “This treatment Lily was not improving. Then, definitely changed our lives.” six years ago, the 12-year-old cat Thus far, the research team at UC joined the first stem-cell clinical Davis has treated 39 cats diag- trial for FCGS. nosed 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 signifi- cantly 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 “Lily,” who is now 18 years old, suffered for three years with painful mouth sores surgically removing all teeth, yet and gums due to FCGS before successful only an estimated 30 percent of treatment with stem-cell therapy.

2 CAT Update

cats experience complete remission, 40 percent sub- stantially improve and 30 percent are unchanged. The cats that do not respond to treatment need lifelong anti- ARZI/UC DAVIS BOAZ DR. SOURCE: biotics as well as painkilling and immunosuppressive drugs. Cats that do not improve often are euthanized. Cats with FCGS have red, Cat Owners Can Help swollen and ulcerated gums Advance FCGS Research and mouth. Painful inflam- mation usually starts around Research at the University of an affected tooth, quickly California-Davis is underway to progressing to nearby tissue learn whether stem-cell therapy until it affects the back of can help cats diagnosed with the mouth, the palatoglossal feline chronic gingivostomatitis arch, and beneath the tongue. FCGS is a severe, inflammatory oral disease that (FCGS) early in the disease pro- Lesions can develop on the is challenging to treat with success. cess. Cats that have been diag- lips, tongue, back of the nosed with FCGS and still have throat, and roof of the mouth. potentially multiple factors, including most of their teeth are eligible Clinical signs include an inability bacterial infections related to exces- to participate. If more than 50 to eat, loss of appetite and weight, sive plaque or periodontal disease, percent of the teeth have been withdrawn behavior, reduced and viral infections such as calici- extracted or need to be extracted, grooming, excessive salivation, , herpes and feline immuno- the cat will not qualify. bloody saliva, bad breath, and deficiency virus. For information about partic- pawing at the mouth. “With stomatitis, like other immune- ipating, please contact Megan Diagnosis requires a dental exam- mediated diseases, the immune Loscar, RVT, or Dr. Boaz Arzi ination to evaluate the oral inflam- system attacks the body’s own tissues,” at 530-752-2470 or by email at mation and ulceration as well as explains Dori L. Borjesson, DVM, [email protected]. periodontal and gum disease. Blood PhD, DACVP, professor of patholo- tests and urinalysis can determine gy, and immunology white blood cell count and con- and director of the Veterinary Institute current diseases. Cats also may be for Regenerative Cures at UC Davis. tested for feline immunodeficiency “One thought is that a virus sets (FIV), feline leukemia (FeLV), bar- up a continuous loop of immune tonella, or other viral infections. responses, triggering the response All cats can develop stomatitis, even after the virus is gone.” but it occurs more commonly in Traditional treatments may not those with compromised immune cure gingivostomatitis and can have systems. “The incidence of FCGS is significant side effects that diminish from 0.7 to 12 percent of cats, or a cat’s quality of life. “These cats from 500,000 to 11 million cats in are suffering,” Dr. Arzi says. “This the U.S.,” estimates Boaz Arzi, DVM, condition works well for stem-cell DAVDC, DEVDC, associate professor research because you can easily see of surgical and radiation services if the treatment is effective by examin- at UC Davis. “I’ve seen more cases ing a cat’s mouth. You also can see from multicat households.” when cats start gaining weight.” Although what causes FCGS is The immune system of a cat with unclear, an inappropriate immune FCGS is essentially working on response is likely involved due to overdrive with little effect. “It’s like

3 SUMMER 2018

WINN FELINE FUNDS FOUR GINGIVOSTOMATITIS CLINICAL TRIALS AT UC DAVIS Winn Feline Foundation, a nonprofit organization that from their own fat tissue, then delivered in two funds feline health research, has supported four stem- intravenous transfusions four weeks apart. Five cell clinical trials at the University of California-Davis cats, or 71 percent, showed significant improve- aimed at helping cats that do not respond to traditional ment or were cured within three to six months. treatment for feline chronic gingivostomatitis (FCGS). Three cats experienced clinical remission. Two “The impact of these studies has been tremendous,” cats did not respond. This study was published in says Vicki L. Thayer, DVM, DABVP (feline), executive January 2016 in Stem Cell Translational Medicine. director of Winn Feline. “Not only has this research • Allogeneic Adipose-Derived Mesenchymal Stem- benefited many cats with FCGS that are refractive Cell Therapy for Syncytial Foamy Virus-Positive to other treatments, it opens the door for broader Cats with Chronic, Nonresponsive Gingivostomatitis application of stem-cell therapy in treating other (2014-2016): Cats with FCGS that also tested positive oral conditions plus many more health problems.” for feline foamy virus, a common that Here are the studies that Winn Feline has funded. does not affect stomatitis but hinders the cultiva- Additional funding to support these studies has come tion of adMSCs in many cats, were the focus from the National Institutes of Health and UC Davis. of this study. Seven cats were treated with two • Autologous Adipose-Derived Mesenchymal Stem- intravenous injections of adMSCs cultured from Cell Therapy for Cats with Chronic, Nonresponsive donor cats. Fifty-seven percent responded Gingivostomatitis (2012-2014): Seven cats com- successfully, with two cats showing significant pleted this clinical trial in which adipose-derived improvement and two that were cured. Three mesenchymal stem cells (adMSCs) were cultivated 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 Gingivosto- matitis (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 in- vasive, 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.

4 CAT Update

“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.” putting a car in neutral and pressing laboratory and then injected into Boaz Arzi, DVM, DAVDC, DEVDC, asso- the gas,” compares Dr. Arzi. “But in cats with FCGS. The studies are ciate professor of surgical and radiation a majority of cats, stem cells jump- among four FCGS stem-cell therapy services, UC Davis. start the immune system, which trials conducted at UC Davis that helps fight the disease.” were funded by Winn Feline Foun- During the stem-cell culture pro- dation, a nonprofit organization cess, the low number of stem cells that supports research devoted to found in the tissues is expanded to feline health and medical problems. a higher number as they grow and All the cats had failed to improve divide. Ultimately, each cat receives previously from full dental extractions 20 million stem cells per treatment. and immunosuppressive drugs. Other cells that are harvested, such However, when they were given as fat cells or endothelial cells, don’t stem cells, up to 70 percent of the survive the culture process. Thus, cats showed substantial or com- the stem cells that are returned to plete resolution of their disease. the patient are pure. The success rate and response “Stem cells are administered to time varied depending on whether patients in a balanced saline fluid,” the MSCs were from the patient explains Dr. Borjesson. “We take low or a donor cat. Some cats still did numbers of these cells that help heal not improve. tissues in a normal repair process A new study has just begun at and deliver high numbers back.” UC Davis testing stem-cell therapy In two consecutive studies, the in FCGS cats that have not yet had UC Davis research team demon- most or all of their teeth extracted. strated that adult adipose-derived Because many cats with stomatitis mesenchymal stem cells could be also have periodontal disease that safely harvested, cultured in the necessitates removing teeth, enrolling

5 SUMMER 2018 future of cats with gingivostomatitis,” he says. The UC Davis stem-cell product is patented for use in oral inflamma- tory 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 veteri- nary 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. Mesen- chymal stem cells that are removed cats in the current study is challenging, from a cat then cultured and injected Dr. Arzi says. Finding an effective back into the same animal are autolo- alternative to total tooth extraction gous cells. Allogeneic cells are will target early intervention. obtained from a donor cat, cultured “Of all the studies we’ve done, I and injected into another cat. think if we can show that stem cells In their initial study, the UC Davis can hold the disease without pro- team used fresh, autologous cells, gression or improve cats’ condition with 71 percent of the cats signifi- without full-mouth extraction, this cantly improving or being cured in will have the biggest effect on the two to six months. Fresh, allogeneic

6 CAT Update cells were used in the second study, T cell, a cytotoxic cell called CD8+, resulting in 57 percent efficacy which helps control viral infections. within six to 20 months. As more “In many of the cats that respond data is collected, Dr. Arzi says, to MSC treatment, CD8+ numbers “the long-term success appears drop,” Dr. Borjesson says. “It’s too to be the same between the two early to know how, but we think types, but autologous is faster.” this is mostly a CD8-driven disease Unfortunately, cats cannot always in cats and that CD8 cells are the provide their own viable stem cells. ones destroying the oral tissues.” The UC Davis team discovered that There are various types of immune “Our allogeneic work is MSCs from approximately half the cells with different functions, and cats in the second clinical study the levels of each one and ratio progressing, and we are could not be cultured because the among them also may affect the cats had feline foamy virus (FFV). disease and outcomes. “These may having many more successes. Relatively common, FFV does not be signs of different causes of sto- harm cats or directly impact sto- matitis,” Dr. Borjesson theorizes. Now we’re seeing more matitis or the efficacy of stem-cell “Perhaps some are not as respon- equality in the effectiveness treatments, but it does hinder the sive to stem-cell treatment. As a cultivation of stem cells. scientist, this is a new way to think of allogeneic and autologous As the research continues, Dr. about what’s causing this disease.” Borjesson says they are beginning “We don’t know what causes stem cells.” to test increased MSC dosages and stomatitis, and we currently do Dori L. Borjesson, DVM, PhD, DACVP, to develop new allogeneic lines. not have an effective treatment,” professor of pathology, microbiology “Our allogeneic work is progress- Dr. Arzi reflects. “Research shows and immunology and director of the ing, and we are having many more that stem cells are a viable alter- Veterinary Institute for Regenerative successes,” he says. “Now we’re native for cats when all else has Cures at UC Davis seeing more equality in the effec- failed. We hope it’s also a better tiveness of allogeneic and autolo- and earlier treatment. Stem-cell gous stem cells.” technology is evolving so rapidly, Also, the investigators say, fresh someday we’ll be engineering stem stem cells are more effective than cells to do exactly the job we want.” frozen stem cell lines, which are Meanwhile, one of the main hopes commonly used in research because of the UC Davis team is to have a of their availability and convenience. better understanding of what defines Fresh MSCs take up to three days to the best conditions for using stem cultivate but lead to fewer adverse cells to treat FCGS. The ability to reactions in cats that receive allo- let clinicians know how to use stem geneic stem-cell transfusions. cells, what to expect and how to get “Fresh cells are favored because consistent results is the motive. we believe much of our efficacy For cats like Lily, who is now 18 data in cats with FCGS and in other years old, it could mean a swifter, ongoing clinical trials are related to more effective treatment without the infusion of freshly expanded the years of pain she experienced. LOOKING TO REPRINT? cells,” says Dr. Borjesson. “We are incredibly thankful for the Another goal of the researchers is stem-cell therapy that Lily had,” Cat Update articles may be to study the mechanisms by which Luke says. “Just to see her feeling reprinted provided the article stem cells regulate immune-cell healthy again was the best part.” n is used in its entirety and in a function. They hope to find bio- positive manner. To request markers or cellular indicators that permission to reprint an article, could help predict which cats are Purina appreciates the support please contact the editor at: likely to respond to MSC therapy. of the Winn Feline Foundation, [email protected]. Blood taken from the FCGS study and particularly Vicki L. Thayer, com. Reprints should include the cats before treatment, for example, DVM, DABVP (feline), executive following attribution: Used with showed an overabundance of a director, in helping to identify permission from the Cat Update, this topic for the Cat Update. killer subtype of immune system Nestlé Purina PetCare.

7 SPRING 2018

TWO CAT SHOWS COMING TO THE PURINA EVENT CENTER IN AUGUST

More than 180 pedigree cats, plus household pets, from all over the country are expected at two back- to-back all-breed cat shows in August at the Purina Event Center. The Midwest T.G.I.F. Fanciers gets underway on Aug. 4, followed by the National Fanciers Association’s show on Aug. 5. The Purina Event Center, located at Purina Farms in Gray Summit, Missouri, one hour from St. Louis, provides a spacious, ideal environment for cat shows.

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CAT PRO CLUB MEMBERS CAN NOW ORDER MERCHANDISE July 31st Is the Deadline for Submitting Weight Circles Purina Pro Club has expanded its redemption program, into your account faster by taking a picture of your allowing cat members to bank their Purina Points for receipt from purchases of eligible Purina on future orders of Purina logo apparel your smartphone or scanning the receipt into your and merchandise plus gift certificates computer and submitting it online. Your Purina Points for retail, restaurants and travel. will show up in your account by the end of the day Members also can still redeem in most cases if uploaded correctly. You can start Purina Points for checks toward submitting receipts now, though once you submit future purchases of Purina brand receipts, you will not be able to mail in any more cat food. weight circles. To get started, click on the link below In addition, be sure to not miss that will take you to helpful tools — instructions and the cutoff of July 31, 2018, for mailing in weight circles. a video — and then log on to your Pro Club account, After this date, weight circles will no longer be accepted, register and begin submitting receipts. as Purina Pro Club is introducing a new receipt submis- sion program will allow you to get your Purina Points GO TO HELPFUL TOOLS

PURINA PRO PLAN INTRODUCES SAVOR WITH PROBIOTICS FOR CATS

Purina Pro Plan recently added guaranteed live probi- and SAVOR Salmon & Rice and Chicken & Rice for- otics to support digestive health to four SAVOR formu- mulas are made with salmon or chicken, respectively, las for adult cats. SAVOR Shredded Blend Salmon & as the No. 1 ingredient. Containing 40-percent protein, Rice and Shredded Blend Chicken & Rice formulas these complete and balanced foods are formulated to help meet an adult cat’s unique nutritional needs. They also contain natural prebiotic fiber sourced from chicory root to promote digestive health and support a cat’s total well-being; vitamin A and linoleic acid, an omega-6 fatty acid, for skin and coat nourishment; and antioxidants to support immune system health.

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