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Stem Cell Trials Using Companion Animal Disease Models

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Stem Cell Trials Using Companion Animal Disease Models TRANSLATIONAL AND CLINICAL RESEARCH Concise Review: Stem Cell Trials Using Companion Animal Disease Models a b ANDREW M. HOFFMAN, STEVEN W. DOW Key Words. Companion animal disease models • Naturally occurring disease • Spontaneous disease models • Canine stem cells • Feline stem cells • Adipose tissue-derived mesen- chymal stem cells • Bone marrow mesenchymal stem cells • Olfactory ensheathing cells • Mesenchymal stem cell neural lineage • Osteoarthritis • Intervertebral disc degeneration • Spinal disc herniation • Spinal cord injury • Dilated cardiomyopathy • Atopic dermatitis • Inflammatory bowel disease • Lymphocytic-plasmocytic colitis • Keratoconjunctivitis sicca • Sjogren’s syndrome • Multiple sclerosis • Meningoencepha- litis of unknown origin • Granulomatous meningoencephalomyelitis • Canine furuncu- losis • Canine perianal fistulas • Crohn’s fistulitis • Rectocutaneous fistulas • End stage renal disease • Feline chronic kidney disease • One Health • Investigational new ani- mal drug aRegenerative Medicine ABSTRACT Laboratory, Department of Studies to evaluate the therapeutic potential of stem cells in humans would benefit from more Clinical Sciences, Cummings realistic animal models. In veterinary medicine, companion animals naturally develop many dis- School of Veterinary eases that resemble human conditions, therefore, representing a novel source of preclinical Medicine, Tufts University, models. To understand how companion animal disease models are being studied for this pur- Grafton, Massachusetts, USA; pose, we reviewed the literature between 2008 and 2015 for reports on stem cell therapies in bCenter for Immune and Regenerative Medicine, dogs and cats, excluding laboratory animals, induced disease models, cancer, and case reports. Department of Clinical Disease models included osteoarthritis, intervertebral disc degeneration, dilated cardiomyopa- Sciences, Colorado State thy, inflammatory bowel diseases, Crohn’s fistulas, meningoencephalomyelitis (multiple University, Fort Collins, sclerosis-like), keratoconjunctivitis sicca (Sjogren’s syndrome-like), atopic dermatitis, and chronic Colorado, USA (end-stage) kidney disease. Stem cells evaluated in these studies included mesenchymal stem- stromal cells (MSC, 17/19 trials), olfactory ensheathing cells (OEC, 1 trial), or neural lineage cells Correspondence: Andrew derived from bone marrow MSC (1 trial), and 16/19 studies were performed in dogs. The Hoffman, D.V.M., D.V.Sc., Large MSC studies (13/17) used adipose tissue-derived MSC from either allogeneic (8/13) or autolo- Animal Internal Medicine, gous (5/13) sources. The majority of studies were open label, uncontrolled studies. Endpoints Regenerative Medicine and protocols were feasible, and the stem cell therapies were reportedly safe and elicited bene- Laboratory, Cummings School of ficial patient responses in all but two of the trials. In conclusion, companion animals with natu- Veterinary Medicine, Tufts University, North Grafton, rally occurring diseases analogous to human conditions can be recruited into clinical trials and Massachusetts 01536, USA. provide realistic insight into feasibility, safety, and biologic activity of novel stem cell therapies. Telephone: 508-887-4589; Fax: However, improvements in the rigor of manufacturing, study design, and regulatory compliance 508-887-4213; e-mail: andrew. will be needed to better utilize these models. STEM CELLS 2016;34:1709–1729 [email protected] Received December 9, 2015; SIGNIFICANCE STATEMENT accepted for publication March 26, 2016; first published online Studies in veterinary medicine which have employed companion animals to evaluate safety and in STEM CELLS EXPRESS April 12, efficacy of stem cells have not been systematically reviewed for the human medical and bio- 2016. medical research community. The goal of this review is to shed light on examples whereby companion animal spontaneous disease models (i.e., veterinary patients) were utilized to study VC AlphaMed Press 1066-5099/2016/$30.00/0 novel stem cell therapies, and to stimulate further discussion on the potential value of these models in multidisciplinary studies for the dual benefit of human and veterinary medicine. http://dx.doi.org/ 10.1002/stem.2377 Available online without sub- by increasingly sophisticated technologies, such as scription through the open INTRODUCTION cell reprogramming, gene editing, rapid whole access option. The health care field is rapidly evolving with genome sequencing, and multimodality imaging increasing importance placed on disease preven- methods that were inaccessible only a few years tion, early detection, reduced invasiveness, and ago. Evidence is now disseminated across the personalization of therapies. Fundamental knowl- globe through vast information channels, increas- edge about disease mechanismsisbeingunraveled ing its potential influence on health care. STEM CELLS 2016;34:1709–1729 www.StemCells.com VC AlphaMed Press AlphaMed 1710 Stem Cell Trials in Companion Animal Diseases Many of these trends are impacting veterinary medicine, stem cell therapies, and to stimulate further discussion on the particular in the companion animal sector [1–5]. Companion role of these models in multidisciplinary studies for the dual animal diseases mirror many human conditions with respect benefit of human and veterinary medicine. to their symptoms, natural history, pathology, gene associa- tions, molecular phenotype, environmental risk factors, and responses to medication [6]. Homology of gene sequences in COMPANION ANIMAL ORIGIN AND DEFINITIONS healthy tissues and tumors is more extensive between “Companion animals” are domesticated animals that have a psy- humans and companion animals (e.g., dogs and cats), than chological bond with their owners. Dogs, for example, appear to between humans and rodents [7–12]. The epigenomic behav- have been domesticated >15,000 years ago in Central Asia ior (e.g., DNA methylation) of canine and human tumor cells about the time when dogs and wolves became genetically dis- strongly resembles each other [13–16]. Thus, data from com- tinct [19]. In the process of domestication, humans and dogs panion animal research have significant potential to illuminate developed mutual cooperation (social tolerance and attentive- disease pathogenesis and mechanisms of treatment resist- ness), for example, [20]. In the ensuing years, dogs and humans ance, while also testing the potential benefits of human- appear to have undergone convergent evolution, with positive ready, but untested therapies. selection of metabolic, neurologic, and cancer associated genes Yet, the inclusion of companion animal disease models in in both species concurrently [21]. For example, interactions multidisciplinary studies lags behind steep gains in knowledge between humans and animals have been shown to induce and technology. This may reflect the gradual pace by which mutual physiologic benefits, mediated in part through oxytocin veterinary medicine emerged from its agricultural roots in the release by both partners in the interaction [22, 23]. 20th century, to become the multifaceted profession of today, Not surprisingly, companion animals are considered family providing health care to companion, laboratory, food and members by people in the U.S. (66.7% for dogs, 56.1% for fiber, and zoo animals, wildlife, and leading efforts in food cats, and 34.5% of horses were considered family members in safety and public health. While medical research has remained 2011) (https://www.avma.org/KB/Resources/Statistics/Pages/ the domain of human physicians and Ph.D.’s who have Market-research-statistics-US-Pet-Ownership-Demographics- employed experimental animal model systems (including Sourcebook.aspx). This concept is further supported by the transgenic animals, injury models, induced infection and high numbers of pets (one for every two people, or one in tumor models, and nonhuman primates), the veterinary pro- three households in U.S.), the enjoyment people derive from fession has developed tremendous knowledge and expertise traveling with pets, on the amount of money people spend in the care and research of companion animals which natu- on pets, and the physical risks that people take to rescue rally develop many of the diseases that researchers attempt pets. Further underscoring their role as family members, to recreate artificially in the laboratory. Thus, while human abuse of companion animals is linked to violence toward chil- and veterinary medical professions have seen tremendous dren, spouses, and the elderly in families [24]. advances in parallel, they interact more obliquely. This is It is the nature of human-animal interactions which defines exemplified by the fact that veterinary research is principally the term companion animal, not the animal species itself. To found in veterinary focused journals, limiting its dissemina- illustrate, animals raised for production of food and fiber includ- tion. The calls for a more multidisciplinary approach to publi- ing pigs, sheep, goats, chickens, and cattle, are not generally cation and access to literature are both timely and important regarded as companion animals. Animals housed in laboratory (i.e., “One Health, One Literature”) [17]. settings or breeding colonies of animals (e.g., with genetic Companion animal disease models are compelling based on mutations) that do not have a specific owner or inhabit a house- their resemblance to human diseases, but their natural com- hold are excluded from this working definition. Animals that are plexity runs
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