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conducted https://vetsci.org https://doi.org/10.4142/jvs.2020.21.e42 12/22 Stem-cell therapy in dogs and cats Table 6. Veterinary clinical stem cell trials in neoplasia Disease Cell therapy No. of dogs Control Evaluation periods/effects Ref. Hemangiosarcoma with pulmonary metastasis hNSCs; IV; 1 × 107 cells 1 dog (stem cell injection with 5-fluorocytosine therapy about 30 days after surgery) No Follow-up until the patient died (105 days); hNSCs/5-FC therapy can improve the quality of dog's life with therapeutic effects and lower side effects [125] Acute large granular lymphocytic leukemia Allogeneic PBHCT; IV; 5 × 106 CD 34+ cells/kg 1 dog No Follow-up for 2 years; considerable clinical benefit over chemotherapy alone. [129] T-cell lymphoma Autologous PBHCT; IV; more than 2 × 106 CD 34+ cells/kg 15 dogs in stem cell group No Follow-up for overall survival of median 239.5 days (range, 4–738 days); PBHCT may be considered as a treatment option for dogs with T-cell lymphoma. [131] B-cell lymphoma Autologous PBHCT; IV; more than 2 × 106 CD 34+ cells/kg 24 dogs in stem cell group No Follow-up for assessment of disease-free interval (median 271 days) and overall survival (median 463 days); PBHCT may be considered as a treatment option for dogs with B-cell lymphoma. [132] hNSC, human neural stem cell; IV, intravenous; PBHCT, peripheral blood hematopoietic cell transplantation. for the treatment of skin or muscle wounds. The results of these studies were also favorable, but they failed to demonstrate objective indicators with only a few clinical cases. Because of the immunomodulatory capacity and paracrine role of some types of stem cells, clinical trials were performed on immune-mediated inflammatory disease such as meningoencephalitis, AD, IBD, anal furunculosis, and FCGS. However, understanding the exact mechanisms of cell therapy for each disease requires further study. In addition, more cases that have clinical, scientific controls and long-term follow-up are needed. Stem cells for the treatment of cancer is an emerging modality in humans, but there is a lack of clinical application in veterinary medicine for evaluation. Because standardized treatment and evaluation methods (including case selection, optimal cell type, delivery route, time of administration, cell dose, evaluation methods, and periods) are not optimized for each trial, treatment efficacy is uncertain and there are always questions that remained unanswered. To use stem cells in clinical therapy, ‘safety’ and ‘efficacy’ are the 2 main issues to consider. In human medicine, there are regulations and guidelines for using stem cell-based products for clinical and commercial use [133]. The basic principles for using cell-based products in veterinary clinical trial should include: 1) Donor selection criteria - The donor should be screened for infectious diseases and other risk factors to prevent the transmission of disease agents. 2) Quality-controlled cells - The origin of the cells, conditions for storage, composition of the products should be adequately defined and labeled. - Demonstration that cellular function and integrity have been preserved. - Prove free of contamination from viruses, bacteria, fungi, mycoplasma and endotoxins. 3) Efficacy and safety - The efficacy and safety of the cells after delivery have been demonstrated in target animals. - Long-term safety evaluation is highly recommended. - Adverse events after stem cell intervention should be reported. - Consider risk factors such as toxicity, tumorigenicity, and immune reactions. Recently, the United States Food and Drug Administration (FDA) and the European Medicine Agency's (EMA) approved guidance for cell-based products for veterinary use [133-135]. In 2018, the Animal and Plant Quarantine Agency (APQA) of Korea also documented ‘Guideline on safety assessment of cell-based products for animal use’ [136]. If researchers and clinicians follow the guidelines of FDA, EMA, and APQA of Korea on the above 3 principles, the problems of standardized treatment protocols and evaluation methods of stem cell therapy will be rapidly improved. Based on the previous pilot and preliminary studies, clinicians' and researchers' efforts to standardize stem cell treatments are needed. In addition, further preclinical and clinical stem cell studies are necessary for the progress of this treatment modality in both human and veterinary medicine. ACKNOWLEDGMENTS The authors thanks to the members of our internal medicine laboratory for their support during drafting of this manuscript. https://vetsci.org https://doi.org/10.4142/jvs.2020.21.e42 13/22 Stem-cell therapy in dogs and cats REFERENCES 1. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143-147. PUBMED | CROSSREF 2. Götherström C. Immunomodulation by multipotent mesenchymal stromal cells. Transplantation. 2007;84(1 Suppl):S35-S37. PUBMED | CROSSREF 3. Mizuno H. Adipose-derived stem cells for tissue repair and regeneration: ten years of research and a literature review. J Nippon Med Sch. 2009;76(2):56-66. PUBMED | CROSSREF 4. Ozawa K, Sato K, Oh I, Ozaki K, Uchibori R, Obara Y, Kikuchi Y, Ito T, Okada T, Urabe M, Mizukami H, Kume A. Cell and gene therapy using
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