Dr. Pedersen Fall 2016 Research Update

We have completed phase 1 of our study with the GC376 protease inhibitor. This study is being done in collaboration with colleagues at Kansas State University.   We have been inundated with requests from owners around the world to have their cats treated, many on the presumption that we have a cure for all cats with FIP.  Phase 1, which is currently being completed and is not open for new cats, was designed to determine the optimal dosage regimen and what forms of FIP and duration of illness will be most responsive to this treatment.  Based on what we have learned from our first group of cats, we know that the treatment will require a minimum of twelve weeks and will cause a rapid reversal of disease signs in most, but not all, cats.  However, we still do not know whether or not we can sustain disease remission in those cats that survive the therapy and remain healthy. Cats with neurologic disease will not respond to this treatment, as the drug does not penetrate well into the brain. We also know that cats with ocular FIP will develop severe neurologic disease during or after treatment.  We have also learned that cats that have had FIP for some time will often develop neurological disease while on treatment or after their initial treatment is completed.  In short, it is not possible to say at this point that a given cat can be “cured” of FIP.  

We would ask that owners not to view our study as a last chance cure for their cat’s disease. This is a preliminary research study using field cases of FIP. Initial results indicate that kittens in the acute stages of effusive (wet) FIP are most likely to go into sustained disease remission and we will therefore concentrate our phase 2 studies on this type of case.  When the time comes for this next phase of our trial we will advertise for more cases under the same strict criteria and owner guidelines employed in our phase 1 study but will not accept any cats that are over this age and/or have other forms of FIP.  We are extremely limited in even the number of kittens with acute effusive FIP that we can accept, so please do not request that your cat be entered into this phase 2 study if it does not meet these new criteria.  Cats will be entered into the study in order of their submission and acceptance. Once we have accepted the number of kittens that are needed, the phase 2 trial will be closed to new cases. The drug is not commercially available and cannot be purchased and must be administered under the institutional and hospital protocols of UC Davis. We understand the desperation that people feel when their cat develops such a terrible disease but our resources are limited and must be strictly focused on the goal of researching FIP what we hope is the first of many highly specific and effective antiviral drugs against FIP virus.  Our study of GC376 is the first step towards that goal and there will hopefully be other promising drugs to be tested in the future. -Dr. Pedersen

 

December 25, 2015

Dear SOCK FIP supporters:

Your support of FIP research at the Center for Companion Animal Health (CCAH) over this last year has been tremendous and much appreciated. This last year has seen a number of advances in our knowledge of FIP and eventual cures. We documented that many cats have a natural resistance to FIP virus, but this resistance increases with age and cannot be explained by simple genetic differences. Rather, resistance is what we call polygenic, and involves many different genetic pathways, any one of which can be used in a given cat at a given time to eliminate the infection. Our research also indicates this immunity is not always permanent and some cats can become susceptible that were once resistant. We learned inbreeding is one of the most important genetic causes of decreased resistance to FIP. We also discovered that the FIP virus attacks only a single cell in the body, a peritoneal-type macrophage, and the infection spreads from macrophage to macrophage and not as free virus in the blood. Virus infected macrophages spread the infection to other organs, and can even enter the brain and eyes in some cats and cause neurologic or ocular disease. Infected macrophages in cats destined to develop FIP also cause a generalized suppression of normal immunity through some sort of signaling, thus assuring the virus’ own survival. Cats that are resistant to FIP do not manifest this suppression.

Finally, and probably of most importance, is our work with antiviral drugs. I am engaged in research with Dr. Yunjeong Kim and her team at Kansas State University on testing a new antiviral drug that strongly suppresses FIP virus replication. This research has gone so well that we will be starting a field trial at UC Davis in late January or February with funds provided by Morris Animal Foundation. This trial will be limited to 70 owned cats with naturally occurring FIP, mainly with wet FIP and a few select cases of dry FIP. Details of this trial will be made public when the time comes to recruit cases for the study. If this drug proves effective against naturally occurring FIP, it will hopefully be taken up by industry and put forward for FDA approval.

I have the fortune of bringing Dr. Brian Murphy, Dr. Chrissy Eckstrand and Dr. Patty Pesavento into our FIP research team. Dr. Pesavento and Dr. Eckstrand will research a highly sensitive test to detect FIP virus with funds from the CCAH that were gifted for FIP research. Dr. Murphy is principal investigator, and I am co-investigator, on a grant from the Winn Feline Foundation to test drugs against FIP virus that are being developed by a leading pharmaceutical company against related coronaviruses causing SARS and MERS in humans. Preliminary studies indicate that many of these drugs will also be active against FIP virus. Therefore, we have entered a new era that might finally see a cure for cats suffering from FIP. The hope is to treat FIP in a manner similar to how antiviral drugs are used to cure people of hepatitis C virus infection.

I have been researching FIP for over 50 years and conclude that this disease is the most complex infection known to man or animal. It has been a tough slog, but we finally understand most of the mysteries of how a ubiquitous and largely innocuous intestinal coronavirus can end up causing such a devastating disease as FIP. There is finally light at the end of the tunnel. Thank you again for your support and patience and have a merry holiday season and we all look forward to good things in 2016.

Sincerely,

Dr. Niels C. Pedersen and colleagues at the UC Davis School of Veterinary Medicine

Some of our members have been interested in the research that has been done in my laboratory concerning FIP. The following is a list of all of the papers that have been published in peer-reviewed journals, as well as two text books that contain important information on FIP as well as other feline infectious diseases and feline husbandry in multiple cat environments. I feel that my laboratory and a number of my students have made significant contributions to our knowledge of FIP. No, we do not yet have a cure or a highly effective strategy to prevent the disease, but we now have a sound basis of knowledge to go forward on a broad front. Efficacious anti-viral drugs will be found against FIP virus, but it will take more time and a lot more money, as anti-viral drug development is extremely expensive. We feel that there is hope in using genetics to increase resistance to the disease. We will ultimately understand how simple mutations in the Feline Enteric Coronavirus can lead to FIP, and how the mutant FIP virus can evade the host’s immune system. Unfortunately, it is my personal opinion that an efficacious vaccine will not be forthcoming.

We have been criticized from time-to-time, and again recently, for the use of laboratory bred cats in some of our research projects. The most recent criticism accuses me of being unethical for the use of laboratory cats in a recent study involving natural immunity to FIP. Unethical was an inappropriate charge, because all animal research is strictly controlled by the USDA and Institutional Animal Use and Care committees to make sure that it is ethically sound. I accept that there are moral differences on this issue and have been consistent in encouraging those opposed to the use of laboratory cats in research to direct their support to those groups and organizations that fund only research on naturally occurring disease. I hope that these people will realize that much of what we have learned from experimental disease has had a direct impact on the conduct and design of studies on naturally occurring disease and vice versa. Finally, FIP research was a lonely undertaking when I first started in 1964. I have reviewed the literature from the first recognition of FIP to 2009, and recently reviewed the FIP literature from 2009 through early 2014. These three review papers have been made freely available to the public on this website. It is noteworthy that there are almost as many researcher publications on FIP during the last 5 years than in the decades that preceded it.

FIP is not a rare disease – it kills thousands of young (and a few old) cats each year and one estimate has linked FIP to as many as 1 in 300 deaths among cats seen at North American veterinary schools. I think that we need to give thanks to the many cats that have died from FIP, both naturally and induced, for their great contributions to our present knowledge of this extremely complex infection. Answers will not come unless people support FIP research, wherever it is being conducted and whether it involves natural or experimental disease, or a combination of both. The simplest contribution would be a buccal swab for DNA from a cat with FIP or an immediate relative.

Abstracts and in many cases full text documents can be found for many of these articles on PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Just type in “Pedersen NC and FIP” or “Pedersen NC and feline coronavirus” in the search space and the articles will appear. If you then click on the title of the article, an abstract will appear if available. If you have open access to a full text article, a link will be present in the upper right hand corner.

Ward, B.C. and Pedersen, N.C.: Infectious peritonitis in cats. Journal of the American Veterinary Medical Association 154:26 35, 1969.

Pedersen, N.C.: Morphologic and physical characteristics of feline infectious peritonitis virus and growth in autochthonous peritoneal cell cultures. American Journal of Veterinary Research 37 (5):567 572, 1976.

Pedersen, N.C.: Feline infectious peritonitis: Something old, something new. Feline Practice 6 (May):42 51, 1976.

Pedersen, N.C.: Serologic studies of naturally occurring feline infectious peritonitis. American Journal of Veterinary Research 37:1447 1453, 1976.

Pedersen, N.C., Theilen, G., Keane, M.A., Fairbanks, L., Mason, T., Orser, B., Chen, C.H., Allison, C.: Studies of naturally transmitted feline leukemia virus infection. American Journal of Veterinary Research 38 (10):1523 1531, 1977.

Pedersen, N.C.: Feline infectious peritonitis test results: What do they mean? Feline Practice, May:13 14, 1977.

Pedersen, N.C., Ward, J. and Mengeling, W.L.: Antigenic relationship of the feline infectious peritonitis virus to coronaviruses of other species. Archives of Virology 58:45 53, 1978.

Woods, R.D., Pedersen, N.C.: Cross protection studies between feline infectious peritonitis and porcine transmissible gastroenteritis viruses. J. Vet. Micro. 4:11 16, 1979.

Pedersen, N.C., Boyle, J.: Immunologic phenomena in the effusive form of feline infectious peritonitis. American Journal of Veterinary Research. 41:868 876, 1980.

Pedersen, N.C., Boyle, J.F., Floyd, K.: Infection studies in kittens utilizing feline infectious peritonitis virus propagated in cell culture. American Journal of Veterinary Research, 42:363 367, 1981.

Pedersen, N.C., Boyle, J.F., Floyd, K., Fudge, A. and Barker, J.: An enteric coronavirus infection of cats resembling transmissible gastroenteritis of swine, and its relationship to feline infectious peritonitis. American Journal of Veterinary Research, 42:368 377, 1981.

Horzinek, M.C., Lutz, H., Pedersen, N.C.: Antigenic relationships among homologous structural polypeptides of porcine, feline, and canine coronaviruses. Infect. Immun. 37:1148 1155, 1982.

Pedersen, N.C., Black, J.W.: Attempted immunization of cats against feline infectious peritonitis using avirulent live virus or sublethal amounts of virulent virus. Am. J. Vet. Res. 44:229 234, 1983.

Boyle, J.F., Pedersen, N.C., Evermann, J.F., McKeirnan, A.J., Ott, R.L., Black, J.W.: Plaque assay, polypeptide composition and immunochemistry of feline infectious peritonitis virus and feline enteric coronavirus isolates. Adv. Exp. Med. Biol. 173:133 147, 1984.

Pedersen, N.C., Black, J.W., Boyle, J.F., Evermann, J.F., McKeirnan, A.J., Ott, R.L.: Pathogenic differences between various feline coronavirus isolates. Adv. Exp. Med. Biol. 173:365 380, 1984.
Pedersen, N.C.: Feline infectious peritonitis and feline enteric coronavirus infections. Part I: Feline enteric coronavirus. Feline Practice 13(4):13 19, 1984.

Pedersen, N.C.: Feline infectious peritonitis and feline enteric coronavirus infections. Part II: feline infectious peritonitis. Feline Practice 13(5):5 14, 1984.

Pedersen, N.C., Evermann, J.F., McKeirnan, A.J., and Ott, R.L.: Pathogenicity studies of feline coronavirus isolates 79 1146 and 79 1683. Am. J. Vet. Res. 45:2580 2585, 1984.

Pedersen, N.C., Floyd, K.: Experimental studies with three new strains of feline infectious peritonitis virus: FIPV UCD2, FIPV UCD3, and FIPV UCD4. Compendium 7:1001 1011, 1986.

Hawkins, E., Johnson, L., Pedersen, N.C., and Winston, S.: Use of tears for the diagnosis of feline leukemia virus infections. J. Am. Vet. Med. Assoc. 188:1031 1034, 1986.

Pedersen, N.C.: Virologic and immunologic aspects of feline infectious peritonitis virus infection. Adv. Exp. Med. Biol., 218:529-550, 1987.

Pedersen, N.C.: Feline Infectious Diseases. American Veterinary Medical Publica¬tions, Goleta, CA, 1988.

Pedersen, N.C.: Animal virus infections that defy vaccination: Equine infectious anemia, caprine arthritis-encephalitis, maedi-visna, and feline infectious peritonitis. Adv. Vet. Sci. Comp. Med. 33:413-428, 1989.

Pedersen, N. C.: Feline Husbandry. Diseases and management in the multiple-cat environment. American Veterinary Pulications, Goleta, CA, 1991.

Vennema, H., Poland, A., Floyd-Hawkins, K. and Pedersen, N.C.: A comparison of the genomes of FECVs and FIPVs and what they tell us about the relationships between Feline Coronaviruses and their Evolution. Feline Practice 23(3):40-44, 1995.

Hickman, M.A., Morris, J.G., Rogers, Q.R., and Pedersen, N.C.: Elimination of feline coronavirus infection from a large experimental specific pathogen-free cat breeding colony by serologic testing and isolation. Feline Practice 23(3):96-102, 1995.

Foley, J.E. and Pedersen, N.C.: Inheritance of susceptibility of feline infectious peritonitis in purebred catteries. Feline Practice 24(1):14-22, 1996.

Poland, A.M., Vennema, H., Foley, J.E. and Pedersen, N.C.: Two related strains of feline infectious peritonitis virus isolated from immunocompromised cats infected with the feline enteric coronavirus. Journal of Clinical Microbiology 34(12):3180-3184, 1996.

Foley, J.E., Poland, A., Carlson, J. and Pedersen, N.C.: Patterns of feline coronavirusinfection and fecal shedding from cats in multiple-cat environments. Journal of the American Veterinary Medical Association 210(9):1307-1312, 1997.

Foley, J.E., Poland, A., Carlson, J. and Pedersen, N.C.: Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus. Journal of the American Veterinary Medical Association 210(9):1313-1318, 1997.

Vennema, H., Poland, A., Foley, J. and Pedersen, N.C.: Feline infectious peritonitis viruses arise by mutation from endemic feline enteric coronaviruses. Virology 243(1):150-157, 1998.

Gut, M., Leutenegger, C.M., Huder, J.B., Pedersen, N.C. and Lutz, H.: One-tube fluorogenic reverse transcription-polymerase chain reaction for the quantitation of feline coronaviruses. Journal of Virological Methods 77(1):37-46, 1999.

Dean GA, Olivry T, Stanton C, Pedersen NC. In vivo cytokine response to experimental feline infectious peritonitis virus infection. Veterinary Microbiology 97:1-12, 2003.

Kiss I, A Poland and NC Pedersen. Disease outcome and cytokine responses in cats immunized with a virulent feline infectious peritonitis virus (FIPV)-UCD1 and challenge-exposed with virulent FIPV-UCD8. Journal of Feline Medicine and Surgery 6:89-97, 2004.

Pedersen NC, Sato R, Foley JE, and Poland AM. Common virus infections in cats, before and after being placed in shelters, with emphasis on Feline Enteric Coronavirus. Journal of Feline Medicine and Surgery 6(2):83-88, 2004.

Pedersen, NC, Lyons LA. Pathogenesis of feline enteric coronavirus infection. J Feline Medicine Surgery, 10(6):225-258, 2008.

Pedersen NC. A review of feline infectious peritonitis virus infection: 1963-2008. Journal of Feline Medicine and Surgery 11(4):225-58, 2009.

Pedersen NC, Liu H,. Dodd KA, Pesavento PA. Significance of Coronavirus Mutants in Feces and DiseasedTissues of Cats Suffering from Feline Infectious Peritonitis. Viruses , 1, 166-184, 2009.

Pedersen NC, Liu H, Scarlett J, Leutenegger CM, Golovko L, Kennedy H, Kamal FM .Feline infectious peritonitis: role of the feline coronavirus 3c gene in intestinal tropism and pathogenicity based upon isolates from resident and adopted shelter cats. Virus Res. 165(1):17-28, 2012.

Golovko L, Lyons LA, Liu H, Sørensen A, Wehnert S, Pedersen NC. Genetic susceptibility to feline infectious peritonitis in Birman cats. Virus Research, 175(1):58-63, 2013.

Pedersen NC. An update on feline infectious peritonitis: diagnostics and therapeutics. Vet J. 201(2):133-41, 2014.

Pedersen NC. An update on feline infectious peritonitis: virology and immunopathogenesis. Vet J. 201(2):123-32, 2014.

Pedersen NC, Liu H, Gandolfi B, Lyons LA. The influence of age and genetics on natural resistance to experimentally induced feline infectious peritonitis. Vet Immunol Immunopathol. 2014 Sep 16. pii: S0165-2427(14)00199-8. doi: 10.1016/j.vetimm.2014.09.001. [Epub ahead of print] PubMed PMID: 25265870.

 

 

 

 

Dr. Pedersen believes that a vaccine for FIP is not possible. Husbandry practices that can reduce the incidence of the disease have been implemented by many catteries and shelters, but will only have a limited effect. Therefore, his laboratory has concentrated on identifying anti-viral drugs that may prolong life, or hopefully bring about a cure. Collaborations have been underway with researchers at Kansas State University on testing the first generation of protease inhibitors. Protease inhibitors constrain and/or impede virus replication and are part of the drug cocktail currently used to treat HIV/AIDS. Preliminary testing of first generation protease inhibitors with activity against FIP virus appears hopeful. Dr. Pedersen is also negotiating with a large pharmaceutical company and researchers at another University to help screen and test a number of compounds that show activity against related viruses that cause SARS and MERS in humans. The goal is to identify several safe and effective drugs that will attack the FIP virus by different mechanisms, mimicking the approach that has been so successful for HIV infection. His research team will also continue to study the nature of FIP immunity and the mechanisms by which the FIP virus is able to evade a cat's defense mechanisms and cause disease. This latter research may identify additional targets for drug therapy.