Psoriasis is a chronic skin disease affecting 2% of the world population. It is characterized by immune infiltrates in lesions and hyperkeratosis, and can be partially remediated with prescription medicines, such as topical retinoids. Despite their great potential, current topical retinoid drugs are typically used at suboptimal doses, due to their side effects. Adverse effects, which include skin irritation, photosensitivity and teratogenicity are common to all 1st and 2nd generation retinoids. While the 3rd generation of retinoids appears to have a better teratogenicity safety profile, its skin-adverse effects such as erythema, scaling, dryness, pruritus, and burning are not improved, affecting 10-40% of patients. In an attempt to discover retinoid-like functional compounds with minimal adverse effects, we screened libraries of natural compounds from plants traditionally used for the treatment of skin diseases, with the emphasis on psoriasis. Our research yielded one product candidate (SBD.073) with desired similar gene expression profile to retinol in human skin substitutes (using DNA microarrays) but without any skin irritation, as determined by repeat insult patch test in humans. In further human studies, SBD.073 has been found to be not only non-irritant and non-phototoxic, but, to the contrary, to protect skin from UV-induced erythema. Mechanistic studies showed that, similarly to retinol, SBD.073 induced F9 cell differentiation and normalized structure of the dermal-epidermal junction, but unlike retinol, it did not stimulate the expression of RARG1 - the receptor implicated in skin irritation. Moreover, this retinoid analogue was found to have an excellent anti oxidant and anti-inflammatory activity and no mutagenicity. Here, we propose to validate the proof of principle that SBD.073 is a unique drug-candidate for a greatly improved topical treatment of psoriasis in a comparative study with the existing topical retinoid treatments. We will use a combination of psoriasis-relevant assays, such as TNF-a and IL-17/IL-22 - stimulated organotypic skin substitutes, and animal models (orthokeratosis in mouse tail test, urticuli normalization in rhino mouse and teratogenesis in NMRI mouse) to demonstrate that SBD.073 exceeds the therapeutic activity of current topical retinoid treatment modalities, while having second- to-none safety and tolerance profile. Taken together, this project should result in the establishment of a proof of principle that SBD.073 is the first skin-protectant retinol analogue fo a greatly improved topical therapy of psoriatic lesions.
Psoriasis is a chronic autoimmune disease affecting millions of people worldwide, in which the immune infiltrates disrupt normal keratinization of the skin. Among the available treatments, retinoids are an important therapeutic option, which is however limited by side effects (retinoid dermatitis, teratogenicity, photosensitivity), which adversely affect the tolerance and patient compliance. Even the more stable, synthetic 3rd generation retinoids, such as adapalene, trigger adverse effects such as erythema, scaling, dryness, pruritus, and burning in 10-40% of patients. Without providing a clear activity gain, better teratogenic profile is their only advantage over the earlier retinoids. Here, we propose to develop a functional analogue of retinoids (named SBD.073), which has been isolated from a traditional medicinal plant used for psoriasis and which has been extensively characterized by our lab in terms of its safety, adverse skin effects as well as skin-normalizing bioactivity, as compared to retinol. From these studies it appears that not only SBD.073 is not a skin irritant, but it protects skin from UV-induced erythema (without being a sunscreen) - an important clinical finding in view of retinoids being used in conjunction with phototherapy. Accordingly, our other clinical case study established SBD.073 to be non-phototoxic. Furthermore, this retinoid analogue is not mutagenic and has better anti-inflammatory properties than retinol, while it retains powerful retinol-like activities - so important in psoriasis treatment - such as the abilit to induce cell differentiation and normalize skin structure by strengthening the dermo- epidermal juncture (basement membrane). Hence, it is reasonable to hypothesize that this compound could be better than any current retinoid treatment for the topical treatment of psoriasis. Here, we propose to test this hypothesis by comparing the activity of SBD.073 to the current topical retinoid therapies in several safety and bioactivity models relevant to psoriasis. This will includ tests on tridimensional skin substitutes stimulated with pro-inflammatory cytokines, 2 mouse models of psoriasis with complementary psoriasis-relevant phenotypes, 1 model of retinoid-induced teratogenicity, as well as phototoxicity and skin irritation tests. If successful, this proect will identify the first bioactive retinoid analogue with skin-protective activity, opening the doorto a new generation of functional retinoids for the improved topical treatment of psoriasis.
|Ma, S; Gobis, K; Swindell, W R et al. (2017) Synthesis and activity of the salicylic acid ester of bakuchiol in psoriasis-surrogate keratinocytes and skin substitutes. Clin Exp Dermatol 42:251-260|