Local Inflammatory Biomarkers and Potential Inflammation-Targeting Therapies in Diabetic Retinopathy

Diabetic retinopathy (DR) is one of the most frequent microvascular complications of diabetes. A large body of evidence supports the role of inflammation in the development and progression of DR. Currently, DR is diagnosed based on the presence of morphological lesions detected on fundus examination. Yet, there are other laboratory or imaging biomarker whose alteration precede DR lesions. This chapter will first briefly explain the role of inflammation in DR pathogenesis and will analyze the molecules involved. Further, it will discuss significant and recent studies that analyzed local laboratory or imaging inflammatory biomarkers in different DR stages. It will then focus on several potential inflammation-targeting therapies which proved to be effective in animal or human studies. Validation of these reviewed biomarkers would allow the identification of patients who do not respond to the current available treatment and could benefit from an adjunctive therapy.

A Case of Autoimmune Myocarditis Treated with IL-17 Inhibition

Myocarditis is defined as inflammation targeting the heart muscle. Autoimmune myocarditis is a subtype of myocarditis that can occur as an isolated entity in which the primary targeted organ is the heart or as part of a systemic autoimmune disease. The pathogenesis of autoimmune myocarditis has been studied using experimental autoimmune myocarditis mouse models. These studies have established the role of TH17 and IL-17 in the development and progression of myocarditis. While IL-17 inhibition has been tested in these mouse models, there are no reported cases of IL-17 inhibitors being utilized in humans to treat autoimmune myocarditis. We report a patient diagnosed with autoimmune myocarditis in the setting of psoriasis treated initially with prednisone and methotrexate without improvement. The patient was then started on an IL-17 inhibitor secukinumab, directly targeting the immune mechanisms found to be responsible for autoimmune myocarditis and its progression as evidenced by the experimental autoimmune myocarditis mouse models. We provide nuclear scan imaging pre- and post-treatment with secukinumab documenting resolution of our patient’s autoimmune myocarditis. This novel case highlighting the success of IL17 inhibition in treating autoimmune myocarditis, a disease with no truly effective treatment and with potentially devastating consequences, provides an exciting avenue for future research in larger patient populations to further assess the efficacy of this treatment modality.

Leptin antagonism inhibits prostate cancer xenograft growth and progression

Hyperleptinaemia is a well-established therapeutic side effect of drugs inhibiting the androgen axis in prostate cancer (PCa), including main stay androgen deprivation therapy (ADT) and androgen targeted therapies (ATT). Given significant crossover between the adipokine hormone signalling of leptin and multiple cancer-promoting hallmark pathways, including growth, proliferation, migration, angiogenesis, metabolism and inflammation, targeting the leptin axis is therapeutically appealing, especially in advanced PCa where current therapies fail to be curative. In this study, we uncover leptin as a novel universal target in PCa and are the first to highlight increased intratumoural leptin and leptin receptor (LEPR) expression in PCa cells and patients' tumours exposed to androgen deprivation, as is observed in patients' tumours of metastatic and castrate resistant (CRPC) PCa. We also reveal the world-first preclinical evidence that demonstrates marked efficacy of targeted leptin-signalling blockade, using Allo-aca, a potent, specific, and safe LEPR peptide antagonist. Allo-aca-suppressed tumour growth and delayed progression to CRPC in mice bearing LNCaP xenografts, with reduced tumour vascularity and altered pathways of apoptosis, transcription/translation, and energetics in tumours determined as potential mechanisms underpinning anti-tumour efficacy. We highlight LEPR blockade in combination with androgen axis inhibition represents a promising new therapeutic strategy vital in advanced PCa treatment.

ALBUMIN-BASED NANOPARTICLES FOR DRUG COMBINATION IN INFLAMMATORY BOWEL DISEASE

Despite recent therapeutic advances in the treatment of inflammatory bowel disease (IBD), the off-target systemic side effects of small-molecule drugs or biologics remain problematic. Targeting the site of intestinal inflammation offers an approach to maximize potential therapeutic benefits while minimizing systemic side effects. Importantly, drug combination provides the possibility of tackling IBD through different pathways that could improve the treatment outcome. Here we introduced an inflammation-targeting drug delivery system utilizing albumin-based nanoparticles (NPs) for drug combination with relevance for IBD treatment. The pathophysiological features of the inflamed mucosa in IBD include the disrupted mucosal barrier and increased intestinal permeability; inflammation of the colonic mucosa is also accompanied by an in-situ secretion and accumulation of positively charged proteins at the site of inflammation 1, 2. We formulated the NPs using human serum albumin (HSA) with heparin coating (termed as HEP-HSA NPs) to increase the negative surface charge to interact with the accumulated positively charged proteins at the inflamed mucosa. Both small-molecule drugs and biologics were chosen to be encapsulated in these NPs, including budesonide (BUD), vancomycin (Vanco), and granulocyte macrophage colony-stimulating factor (GM-CSF). As an example of drug combination, we loaded BUD and GM-CSF simultaneously in the HEP-HSA NPs. The dual-drug loaded HEP-HSA NPs exhibited a higher anti-inflammatory effect than both of the single-drug loaded NPs in vitro and selectively bound to the inflamed intestine after enema administration in vivo in a murine model of colitis. Importantly, analyses of the physicochemical characteristics and targeting capacities of these NPs indicate that HEP coating modulates NP binding to the inflamed intestine, providing a foundation for future development of inflammation-targeting NP formulations 3. Furthermore, by analyzing disease parameters in individual mice, we also investigated the correlation between NP targeting and disease activity in the inflamed colon, which provides an approach to further our understanding on the underlying interactions between NPs and the biological interface in colitis. References: 1. Tirosh B, Khatib N, Barenholz Y, et al. Transferrin as a luminal target for negatively charged liposomes in the inflamed colonic mucosa. Mol Pharm 2009;6:1083–91. 2. Zhang S, Ermann J, Succi MD, et al. An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease. Sci Transl Med 2015;7:300ra128. 3. Zhang S, Cho WJ, Jin AT, et al. Heparin-Coated Albumin Nanoparticles for Drug Combination in Targeting Inflamed Intestine. Adv Healthc Mater 2020;9:e2000536.

Novel Analgesics with Peripheral Targets

A limited number of peripheral targets generate pain. Inflammatory mediators can sensitize these. The review addresses targets acting exclusively or predominantly on sensory neurons, mediators involved in inflammation targeting sensory neurons, and mediators involved in a more general inflammatory process, of which an analgesic effect secondary to an anti-inflammatory effect can be expected. Different approaches to address these systems are discussed, including scavenging proinflammatory mediators, applying anti-inflammatory mediators, and inhibiting proinflammatory or facilitating anti-inflammatory receptors. New approaches are contrasted to established ones; the current stage of progress is mentioned, in particular considering whether there is data from a molecular and cellular level, from animals, or from human trials, including an early stage after a market release. An overview of publication activity is presented, considering a IuPhar/BPS-curated list of targets with restriction to pain-related publications, which was also used to identify topics.