Abstract
Diabetes mellitus is one of the major concerns for health care systems, affecting 382 million people worldwide. Among the different complications of diabetes, lower limbs chronic ulceration is a common, severe and costly cause of morbidity. Diabetic foot ulcers are a leading cause of hospitalization in diabetic patients and its rate exceed the ones of congestive heart failure, depression or renal disease. Diabetic non-healing ulcers account for more than 60% of all non-traumatic lower limb amputations and the five-year mortality after amputation is higher than 50%, being equal to several types of advanced cancer. The primary management goals for an existing diabetic foot ulcer are to achieve primary healing as expeditiously as possible and to achieve a reduction of the amputation rate in the patients. Unfortunately, approximately a quarter of patients do not partially or fully respond to the standard of care. Advanced therapies for chronic wounds are existing, however, recent guidelines including the latest reviews and meta-analyses of the scientific and clinical evidence available from current treatment strategies and new therapeutic agents revealed that there is a lack of clinical data and persistent gap of evidence for many of the advanced therapeutic approaches. In addition, no pharmacological wound healing product has gained authority approval for more than 10 years in both US and EU, constituting a highly unmet medical need. In this publication we present data from a live biopharmaceutical product AUP1602-C designed as a single pharmaceutical entity based on the non-pathogenic, food-grade lactic acid bacterium Lactococcus lactis subsp. cremoris that has been genetically engineered to produce human fibroblast growth factor 2,interleukin4 and colony stimulating factor 1. Designed to address different aspects of wound healing (i.e. fibroblast proliferation, angiogenesis and immune cell activation) and currently in phase I clinical study, we show how the combination of the individual components on the wound micro-environment initiates and improves the wound healing in chronic wounds.
Highlights
Diabetes mellitus (DM) is a major concern for health care systems
The recombinant LBP AUP1602-C has been designed as a single therapeutic entity based on the non-pathogenic lactic acid bacterium L. lactis subspec. cremoris that has been genetically engineered to produce the human cytokines and growth factors FGF-2, IL-4 and CSF-1
AUP1602-C addresses different aspects of wound healing simultaneously, namely fibroblast proliferation, angiogenesis and immune cell activation, which are distorted in the chronic inflammatory wounds
Summary
In 2019 463 million adults worldwide were affected, and the number of the people with DM is estimated to rise to 700 million by 2045 [1–3] Patients with DM have an increased risk of further complications such as nephropathy, retinopathy, cardiovascular diseases or peripheral neuropathy, which in turn can contribute to the development of diabetic foot ulcers (DFUs) [4, 5]. Chronic ulceration is the most frequently occurring complication of DM with a lifetime incidence of DFU of between 19 and 34% in DM patients [1, 6, 7]. On the basis of 2017 prevalence data from the International Diabetes Federation, Armstrong et al estimated that foot ulcers are developed annually in slightly more than in 2% DM patients and between 5–7.5% in patients with neuropathy worldwide [1]. Non-healing diabetic ulcers account for more than 60% of all non-traumatic lower limb amputations [9]. The five-year mortality after diabetes-related amputation is 30.5%, closely equalling pooled 5-year survival of all reported cancer cases at 31% [10]
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