Safety Profile Evaluation of an Original Mesenchymal Stromal Cell Secretome-Based Medicinal Product after Intratesticular Injection in Rabbits

INTRODUCTION. This work is a continuation of the studies of an original biological product based on the secretome of human mesenchymal stromal cells (MSCs) and intended for the restoration of spermatogenesis and fertility. To ensure the safety of the product, it is necessary to conduct preclinical studies in two types of animals, including rodents (the results of rodent studies were presented earlier) and non-rodents. AIM. This study aimed to investigate the systemic toxicity, safety pharmacology, pyrogenicity, immunotoxicity, reproductive toxicity, and local tolerance of the original MSC secretome product in mature rabbits after two injections under the tunica albuginea of the testes. MATERIALS AND METHODS. The study was conducted in 50 male Soviet chinchilla rabbits (5 groups of 10 animals). The lyophilised MSC secretome product (MediReg) was reconstituted, mixed with collagen gel (Applicoll), and administered to rabbits subalbugineally on days 1 and 28 at a dose equal to the therapeutic dose (≥0.76 ng of vascular endothelial growth factor (VEGF)), 1.5 therapeutic doses (≥1.14 ng of VEGF), or 2.5 therapeutic doses (≥1.9 ng of VEGF). The control groups included intact rabbits and rabbits that received Applicoll mixed with water for injection. The animals were assessed in terms of their clinical condition, body temperature, electrocardiogram changes, heart and respiratory rates, blood pressure, modified Irwin test results, urinalysis findings, blood counts and biochemistry, haemostasis parameters, arterial blood gas measurements, and spermogram changes. Further, the animals were necropsied, and selected organs were weighed and subjected to histopathology. The follow-up period was 60 days. RESULTS. On day 3, the groups receiving 1.5 and 2.5 therapeutic doses of the medicinal product demonstrated a significant decrease in prothrombin time; however, only the placebo group still had decreased prothrombin time levels during the follow-up period. The histological examination revealed occasional splitting areas in the intertubular connective tissue with the formation of cavities filled with a loose substance with pronounced eosinophilic staining and deformation of the tubules along the walls of the cavities as a result of compression in 1–2 of 5 (20–40%) rabbits in all groups that received either the medicinal product or placebo. This was probably caused by mechanical compression of the tubules by the administration of large volumes of substances. In the placebo group, 2 of 5 (40%) animals had a transient increase in the size of the vesicular glands; the lobules were markedly expanded and contained a transparent secretion. The histological appearance of the vesicular glands was normal. CONCLUSIONS. When administered twice under the tunica albuginea of the testes of rabbits, the medicinal product comprising the MSC secretome and the Applicoll collagen gel carrier has an acceptable safety profile.