[unreadable] DESCRIPTION (provided by applicant): This STTR Phase I proposal is directed at the development of a topical treatment for mild psoriasis. It is based on the recent discovery of a cell signaling module important for the regulation of keratinocyte proliferation and differentiation. This signaling module is centered on the enzyme phospholipase D2 (PLD2). PLD2 normally hydrolyzes cell membrane phospholipids. However, in the presence of a primary alcohol, PLD2 can catalyze a transphosphatidylation reaction to generate phosphatidylalcohols. In particular, PLD2 acts to convert glycerol, which gains intracellular access through the aquaporin transporter channel AQP3, into phosphatidylglycerol (PG). PG appears to be involved in at least two important functions: inhibition of keratinocyte proliferation and promotion of epidermal barrier function. In particular, it has been demonstrated that PG normalizes keratinocyte growth in vitro. Psoriasis is characterized by abnormal keratinocyte growth, and evidence points to a breakdown in the glycerol- AQP3-PLD2-PG signaling module. Direct application of PG to psoriatic skin should circumvent the signaling breakdown and help to inhibit epidermal hyperplasia. The overall goal of this proposal is the development of a PG-based psoriasis therapy, both for use as a standalone topical treatment and for use in conjunction with 1,25-dihydroxyvitamin D3 analogs. In the latter case, PG may have the added advantage of countering the irritation from breakdown of skin barrier function caused by vitamin D3 analogs. The Phase I specific aims are: (i) development of a suitable PG treatment formulation, and (ii) initial mouse studies to evaluate efficacy. This involves screening candidate PG structures in a keratinocyte cell culture system to identify a PG analog that maximizes anti-proliferative potency, adapting the selected PG analog to an existing topical delivery vehicle, and comparison of three topical therapies-PG monotherapy, PG/1,25(OH2)D3 combination therapy and 1,25(OH2)D3 monotherapy (as a positive control) vs. vehicle alone (as a negative control)-in tape stripped and irritant contact mouse models. Use of both models allows a delineation of treatment effects toward epidermal hyperplasia and inflammation. In addition, the effect on barrier function will be assessed by measurement of transepidermal water loss (TEWL). The Phase I success criteria are the identification of a PG analog that inhibits keratinocyte growth by = 50% in vitro and demonstration of a significant (p = 0.05) reduction in proliferation and/or inflammation with either PG monotherapy or PG/1,25(OH2)D3 combination therapy relative to vehicle alone in the mouse models. If successful, a follow-on Phase II proposal will be submitted to conduct definitive animal studies of efficacy, dosing and toxicity. Psoriasis is a chronic skin disease affecting approximately 2% of the worldwide population. In the US alone there are an estimated 4.5 million diagnosed cases with an estimated annual cost of care between $650 million and $4.7 billion. Unfortunately, most of the current treatment options are either only moderately effective or have significant side-effects. An effective, easy-to-use, low-cost therapy suitable for long-term relief would be a great boon. [unreadable] [unreadable] [unreadable] [unreadable]
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