Abstract
A cell-free approach using secretomes derived from stem cells or peripheral blood mononuclear cells is an active area of regenerative medicine that holds promise for therapies. Regulatory authorities classify these secretomes as biological medicinal products, and non- clinical safety assessment thus falls under the scope of ICH S6. A secretome of stressed peripheral blood mononuclear cells (APOSEC) was successfully tested in a toxicology program, supporting clinical use of the new drug candidate. Here, to allow for topical, dermal treatment of patients with diabetic foot ulcer, several non-clinical safety studies were performed. Acute toxicity (single dose) and neuropharmacological screening were tested intravenously in a rat model. Risk for skin sensitisation was tested in mice. A 4-week intravenous toxicity study in mice and a 4-week subcutaneous toxicity study in minipigs were conducted to cover the clinical setting and application in a rodent and a non-rodent model. Acute and repeated-dose toxicity studies show that APOSEC administered intravenously and subcutaneously does not involve major toxicities or signs of local intolerance at levels above the intended total human maximal dose of 3.3 U/kg/treatment, 200 U/wound/treatment, and 100 U/cm2/treatment. The non-clinical data support the safe topical use of APOSEC in skin diseases related to deficient wound healing.
Highlights
A cell-free approach using secretomes derived from stem cells or peripheral blood mononuclear cells is an active area of regenerative medicine that holds promise for therapies
Studies show that the regenerative therapeutic effects seen after administration of stem cells in acute myocardial infarction are mediated via paracrine signalling rather than by direct cellular interactions[1,6]
A cell-free product derived from peripheral blood mononuclear cells (PBMCs) instead if stem cells has some advantages compared to advanced therapy medicinal products (ATMPs) (Fig. 1)
Summary
A cell-free approach using secretomes derived from stem cells or peripheral blood mononuclear cells is an active area of regenerative medicine that holds promise for therapies. Regulatory authorities classify these secretomes as biological medicinal products, and non- clinical safety assessment falls under the scope of ICH S6. Autologous APOSEC was tested in a randomised phase I safety and tolerability study, MARSYAS I (ClinicalTrials.gov Identifier: NCT02284360) This autologous APOSEC was produced under Good Manufacturing Practice (GMP) conditions and applied topically in healthy volunteers in combination with NuGel, as described in Simader et al.[15]. APOSEC was administered topically with hydrogel as carrier in non-clinical wound-healing models[9,10], mimicking the intended route of administration in humans
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