Establishing the clinical potential of sphingomimetics in children’s eczema
Chief Investigator: Dr Kwok Ho Yip
Funding Amount: $74,888
Recipient: University of South Australia
Eczema is a long-term inflammatory skin disease that affects 15-30% of children in industrialised countries, leading to a considerable economic burden and reduction in quality of life. The mainstay of treatment has been topical corticosteroids, which has limited efficacy in moderate-to-severe disease and children with steroid-resistance. More importantly, steroid can lead to substantial adverse side effects in children. The objective of our proposal is to provide a scientific basis for the development of new treatment strategies using our recently developed sphingomimetics to suppress the functions of key effector immune cells (e.g. mast cells) for the treatment of eczema in children.
Researchers: Dr Kwok Ho, Dave, Yip, Prof Stuart Pitson, Dr Jo Woodcock, Dr William Smith
Research Completed: 2022
Research Findings: Eczema is a long-term inflammatory skin disease, and current treatment has limited efficacy in moderate-to-severe diseases and patients with steroid resistance. Our study provides a scientific basis for developing new treatment strategies using our recently developed sphingomimetics to suppress the functions of key effector immune cells, mast cells, for the treatment of eczema.
Eczema is the most common long-term inflammatory skin disease of childhood, affecting up to 30% of children in Western countries and is responsible for most paediatric dermatological admissions. Eczema is often manifesting early in life and is known to be the first disease from the “atopic march”, where eczema remission or exacerbation is correlated with the highest risk for developing allergic rhinitis, food allergy and asthma. Therefore, the development of an effective treatment for eczema and subsequent atopic march would represent a significant public health advance. The underlying causes of eczema include genetic and immunological factors. However, an increase in mast cells (an immune cell that plays a crucial role in allergic responses) activation occurs in regions of inflamed skin in patients with eczema, and mast cell numbers are correlated with the severity of the disease. Upon activation, mast cells release a vast array of powerful biological mediators that drive skin inflammation and recruit immune cells into the dermis to intensify disease. Therefore, restraining this mast cell response is vital in devising new therapeutic strategies for eczema.
Finding support from Channel 7 Children Research Foundation boosted our development of a new class of small molecule inhibitor that mimic sphingosine and inhibits the function of a protein called 14-3-3. We first proved that sphingomimetics demonstrated a strong potency in blocking mouse mast cell activation in cell-based experiments. We next sought to understand the translation value of the inhibitor through different mouse models that resemble immediate- and delayed-types of skin allergic hypersensitivity responses. In the immediate-type skin allergic responses model, topical application of the sphingomimetics on mouse ear skin effective inhibited the mast cell-mediated skin inflammatory responses. We confirmed that gene and protein expression of various mast cell mediators such as histamine and a panel of inflammatory cytokines was significantly reduced under sphingomimetics treatment. This also correlated with the decreases in subsequent immune cells’ arrival at the site of inflammation. In the delayed-type skin allergic responses that study the allergic responses when subjects re-expose to the same allergen, we found that the topical application of sphingomimetics was able to suppress skin inflammation induced by the allergen in both prophylactic (applied before allergen re-exposure) and therapeutic (applied after allergen re-exposure) studies. More importantly, under this long-term skin inflammation model, we discovered that sphingomimetics’ action is not limited to mast cells but other immune cells, such as CD8+ T cells, that participate in the exacerbation of the inflammatory response.
Our data demonstrate that sphingomimetics suppress the activity of mouse mast cells in both cell- and animal-based experiments. It remains unknown if the sphingomimetics displays similar potency in eczema patients’ mast cells, whereas their mast cells were reported to have enhanced levels of intrinsic granule mediators and increased mediator releases. Our comparison of human mast cells from allergic disease patients and healthy control confirmed a more robust activity of mast cells from the patients in responses to allergen stimulation. More importantly, we also found that the activity of mast cells is positively correlated with the level of 14-3-3 protein in their serum. Finally, targeting mast cell activation from patients with high 14-3-3 levels with sphingomimetics demonstrated a better outcome than mast cells from low 14-3-3 levels patients and control subjects, which could be further developed as a basis for patient selection and personalised medicine. Eczema remains a significant health problem, especially in children, and needs better long-term management. Despite the use of emollients in combination with topical corticosteroids being the mainstay topical treatments for eczema, the many concerns from clinicians and patients over their use are significant and comprise an everyday challenge in dermatology. Our findings define the efficacy of the sphingomimetics on immediate and delayed allergic skin inflammation in animal models. We also develop a translational roadmap for our findings using clinical samples from allergic disease patients. Our result highlights the importance of diagnostic tests on 14-3-3 levels to guide the optimal delivery of therapeutics to patients. This study, therefore, reveals previously unappreciated functions of 14-3-3 on the regulation of skin inflammation and provides a basis for the development of new treatment strategies using sphingomimetics for the treatment of eczema. We envision that this study will provide an impetus for us to design future clinical trials using sphingomimetics for eczema treatment.
Kwok Ho Yip, Jessica Chao, Carl Coolen, Harshita Pant, William Smith, Quenten Schwarz, Stuart Pitson, Angel F. Lopez, Joanna Woodcock, Damon Tumes. Targeting the pSer/Thr binding adaptor protein 14-3-3ζ to attenuate IgE-mediated mast cell activation and allergic inflammation.
Conference Presentation Establishing the potential of a sphingosine mimetic, RB-011, as an inhibitor of allergic diseases. European Academy of Allergy and Clinical Immunology Congress 2018, Munich, Germany. (Abstract Prize Winner)
Future Outcomes: We anticipate that identifying 14-3-3 as a stratification biomarker in patient serum and novel targetable therapeutic with our sphingomimetics for allergic diseases will result in significant new intellectual properties where AI Woodcock and AI Pitson are well-placed to protect, strengthen and commercialise.