Introduction: Chronic, nonhealing skin wounds claim >3% of the health-care budget in industrialized countries, and the incidence is rising. Currently, two parallel trends influence innovations within the field of wound healing: the need to reduce spread of antibiotic resistance and the emerging use of health economy and value-based models. Areas covered: This review focuses on the discovery of drug candidates and development of treatments aiming to enhance wound healing in the heterogeneous group of patients with nonhealing wounds. Expert opinion: Nonhealing wounds are multifaceted and recognized as difficult indications. The majority of products currently in use are medical device dressings, or concepts of negative pressure or hyperbaric oxygen treatment. Global best practice guidelines for the treatment of diabetic foot ulcers recommend debridement, redressing, as well as infection control, and are critical to the lack of coherent clinical evidence for many approved products in active wound care. To accelerate wound healing, there is an emerging trend toward biologics, gene therapy, and novel concepts for drug delivery in research and in the pipeline for clinical trials. Scientific delineation of the therapeutic mechanism of action is, in our opinion, vital for clinical trial success and for an increased fraction of medical products in the pharmaceutical pipeline.
Non-healing wounds are a growing medical problem and result in considerable suffering. The lack of pharmaceutical treatment options reflects the multistep wound healing process, and the complexity of both translation and assessment of treatment efficacy. We previously demonstrated accelerated healing of full-thickness wounds in mice following topical application of the probiotic bacteria Limosilactobacillus reuteri R2LC transformed to express CXCL12. In this study, safety and biological effects of a freeze-dried formulation of CXCL12-producing L. reuteri (ILP100) were investigated in induced full-thickness wounds in minipigs, and different wound healing evaluation methods (macroscopic, planimetry, 2D-photographs, 3D-scanning, ultrasound) were compared. We found that treatment with ILP100 was safe and accelerated healing, as granulation tissue filled wound cavities 1 day faster in treated compared to untreated/placebo-treated wounds. Furthermore, evaluation using planimetry resulted in 1.5 days faster healing than using 2D photographs of the same wounds, whereas the areas measured using 2D photographs were smaller compared to those obtained from 3D scans accounting for surface curvatures, whereas ultrasound imaging enabled detailed detection of thin epithelial layers. In conclusion, topical administration of the drug candidate ILP100 warrants further clinical development as it was proven to be safe and to accelerate healing using different evaluation methods in minipigs.
Introduction In USA and Europe, it is estimated that more than 3 million people are suffering from inflammatory bowel disease (IBD) and another 1.7 million cancer patients treated with checkpoint inhibitors (ICI) are diagnosed with manifest ICI‐induced colitis. The current treatments with steroids and available biologics act systemically and possess limitations with loss of response and severe adverse events and may even limit the effect of the ICI therapy. Thus, new local‐acting therapies are needed to serve the full unmet need amongst these patients. We have recently published that oral administration of L. reuteriR2LC to mice increases IgA production in Peyer’s patches, resulting in modified gut microbiota, altered physiology and immune cell phenotype in the colon and prophylactic administration reduced inflammation in the DSS‐induced colitis. Methods , the novel drug candidate, ILP100, which is a genetically modified lactic acid bacteria that express the chemokine CXCL12 were generated and evaluated as a therapeutic in two different models of colitis, the DSS‐model and a model of checkpoint inhibitor induced colitis (using aPD1 and aPDL1). Results , Peroral administration of ILP100 to mice with overt colitis interrupts disease progression and improves symptoms assessed as disease activity index (DAI) and colon shortening. Further analysis showed that treatment with ILP100 increased infiltrating immune cells expressing TGF‐ß and IL‐10 as well as other tolerogenic immune cell populations including Treg and Tr1 in the colonic lamina propria. There were no changes in the small intestinal lamina propria or mesenteric lymph nodes and there was no systemic exposure detected. Further, efficacy comparison studies demonstrate a reduced severity and a faster recovery of the ILP100 treated mice compared to TNF‐α inhibitor and α4β7‐inhibitor treated mice. The findings have been confirmed over a large dose range. Even though the ICI‐induced colitis did not manifest in symptoms such as body weight loss or blood in feces, fibrosis was developed measured as a reduction of the mean colon length of 12‐18 % in the ICI‐treated groups compared to control, with a tendency to a reduced colon shortening in the ICI + ILP100‐treated groups. Histological analysis of intestines samples from the checkpoint inhibitor is currently ongoing. In conclusion , we demonstrate that peroral administration of ILP100 efficiently ameliorate overt colitis in the DSS‐model by inducing healing through a local shift into an anti‐inflammatory and tolerogenic immune signature in the colon mucosa. Further, our data suggest that peroral administration of ILP100 ameliorate colitis in an ICI model.
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