Unravelling drivers of cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa.

Epidermolysis bullosa (EB) is an umbrella term for a group of rare inherited skin disorders characterised by mucocutaneous fragility. Patients suffer from blisters and chronic wounds that arise spontaneously or following minor mechanical trauma, often resulting in inflammation, scarring and fibrosis due to poor healing. The recessive form of dystrophic EB (RDEB) has a particularly severe phenotype and is caused by mutations in the COL7A1 gene, encoding the collagen VII protein, which is responsible for adhering the epidermis and dermis together. One of the most feared and devastating complications of RDEB is the development of an aggressive form of cutaneous squamous cell carcinoma (cSCC), which is the main cause of mortality in this patient group. However, pathological drivers behind the development and progression of RDEB-associated cSCC (RDEB-cSCC) remain somewhat of an enigma, and the evidence to date points towards a complex process. Currently, there is no cure for RDEB-cSCC, and treatments primarily focus on prevention, symptom management and support. Therefore, there is an urgent need for a comprehensive understanding of this cancer's pathogenesis, with the aim of facilitating the discovery of drug targets. This review explores the current knowledge of RDEB-cSCC, emphasising the important role of the immune system, genetics, fibrosis, and the tumour-promoting microenvironment, all ultimately intricately interconnected.

Revolutionising healing: Gene Editing's breakthrough against sickle cell disease.

Recent advancements in gene editing illuminate new potential therapeutic approaches for Sickle Cell Disease (SCD), a debilitating monogenic disorder caused by a point mutation in the ß-globin gene. Despite the availability of several FDA-approved medications for symptomatic relief, allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole curative option, underscoring a persistent need for novel treatments. This review delves into the growing field of gene editing, particularly the extensive research focused on curing haemoglobinopathies like SCD. We examine the use of techniques such as CRISPR-Cas9 and homology-directed repair, base editing, and prime editing to either correct the pathogenic variant into a non-pathogenic or wild-type one or augment fetal haemoglobin (HbF) production. The article elucidates ways to optimize these tools for efficacious gene editing with minimal off-target effects and offers insights into their effective delivery into cells. Furthermore, we explore clinical trials involving alternative SCD treatment strategies, such as LentiGlobin therapy and autologous HSCT, distilling the current findings. This review consolidates vital information for the clinical translation of gene editing for SCD, providing strategic insights for investigators eager to further the development of gene editing for SCD.

Topical gene editing therapeutics using lipid nanoparticles: 'gene creams' for genetic skin diseases?

Patients living with inherited skin diseases have benefited from recent advances in DNA sequencing technologies that provide new or improved diagnostics. However, developing and delivering new treatments for the 'genodermatoses' remains challenging. The goal of creating topical preparations that can recover the inherent gene pathology remains largely aspirational. However, recent progress in two fields - the chemistry of topical delivery formulations (lipid nanoparticles) and the molecular biology of gene repair (CRISPR-Cas9, base and prime editing) - presents new opportunities to address this unmet need. In this review, we discuss how lipid nanoparticle delivery vehicles could be used to deliver gene-editing tools to formulate topical 'gene creams' suitable for the treatment of genodermatoses. We summarize the historical landscape of topical therapeutics and advances in gene editing that may herald an era of new therapies for patients with inherited skin disorders.

Concentrations of Selected Adipocytokines in the Blood Plasma in Proximal Suspensory Desmopathy of Horses, with a Focus on Their Physical Activity-A Pilot Study.

Chronic tendon and ligament diseases are commonly encountered in both athletic humans and animals, especially horses. Distal limb diseases, including suspensory ligament (SL) pathology due to anatomical, histological, and biomechanical properties, can be considered a model for tendon and ligament pathologies in humans. The appropriate selection of therapy is often crucial in optimising the healing process. One decisive factor influencing the possibility of returning to pre-disease training levels appears to be the utilisation of physical activity, including controlled movement, during the rehabilitation process. In the pathogenesis of musculoskeletal diseases and rehabilitation, adipocytokines play diverse roles. However, it is unclear what significance they hold in horses and in specific disease entities as well as the consequences of their mutual interactions. Recent studies indicate that in the pathogenesis of diseases with varied aetiologies in humans, their value varies at different stages, resulting in a diverse response to treatment. The results of this study demonstrate lower resistin concentrations in the venous blood plasma of horses with proximal suspensory desmopathy (PSD), while higher levels were observed in regularly trained and paddocked animals. The horses investigated in this study showed higher concentrations of resistin and IL-8, particularly in paddocked horses as well as in the working group of horses. The results suggest that these concentrations, including resistin in blood plasma, may be clinically significant. This attempt to explore the aetiopathogenesis of the processes occurring in the area of the proximal attachment of the suspensory ligament may optimise the procedures for the treatment and rehabilitation of horses.