Inhibition of Sebum Production with the Acetyl Coenzyme A Carboxylase Inhibitor Olumacostat Glasaretil.

Olumacostat glasaretil (OG) is a small molecule inhibitor of acetyl coenzyme A (CoA) carboxylase (ACC), the enzyme that controls the first rate-limiting step in fatty acid biosynthesis. Inhibition of ACC activity in the sebaceous glands is designed to substantially affect sebum production, because over 80% of human sebum components contain fatty acids. OG inhibits de novo lipid synthesis in primary and transformed human sebocytes. TrueMass Sebum Panel analyses showed a reduction in saturated and monounsaturated fatty acyl chains across lipid species, including di- and triacylglycerols, phospholipids, cholesteryl esters, and wax esters in OG-treated sebocytes. There was no shift to shorter acyl chain lengths observed, suggesting that the fatty acid chain elongation process was not affected. OG is a pro-drug of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid and was designed to enhance delivery in vivo. Topical application of OG but not 5-(tetradecyloxy)-2-furoic acid significantly reduced hamster ear sebaceous gland size, indicating that this pro-drug approach was critical to obtain the desired activity in vivo. High-performance liquid chromatography analyses of hamster ear extracts showed that OG treatment increased ACC levels and the ratio of acetyl-CoA to free CoA in these animals, indicating increased fatty acid oxidation. These changes are consistent with ACC inhibition. Matrix-assisted laser desorption/ionization imaging showed that OG applied onto Yorkshire pig ears accumulated in sebaceous glands relative to the surrounding dermis. Sebaceous gland ACC represents an attractive therapeutic target given its central role in formation of sebum, a key factor in acne pathogenesis.

Effects of topically applied acitretin in reconstructed human epidermis and the rhino mouse.

Oral acitretin is currently indicated for the treatment of severe psoriasis in adults, but its use is limited by systemic side effects and teratogenicity. Topical administration of acitretin may lessen the risk of systemic toxicity while increasing local bioavailability in the skin. The effects of topical acitretin on reconstructed human epidermis (RHE) and Rhino mice were investigated and compared to those of currently marketed topical retinoids: tretinoin and tazarotene. In acitretin-treated RHE cultures, there was a reduction in keratohyalin granules and filaggrin expression in the stratum granulosum, a loss of keratin 10 expression in the stratum spinosum, and an increase in keratin 19 expression in all viable cell layers. All retinoids showed similar signs of activity in RHE cultures. Furthermore, the release of pro-inflammatory cytokines IL-1alpha and IL-8 in RHE cultures was less pronounced with acitretin compared to tretinoin- and tazarotene-containing formulations, suggesting that acitretin may be less irritating. In Rhino mice, acitretin induced a local, dose-dependent reduction in utricle diameter after seven daily dermal doses. A similar effect was observed in tretinoin- and tazarotene-treated mice. Our data suggest that topical application of acitretin may have a therapeutic benefit in the local management of keratinization disorders.

Mouse skin models for carcinogenic hazard identification: utilities and challenges.

This report addresses 1) the predictability of mouse skin models for carcinogenic hazard identification, 2) the association between early changes in the skin and later tumorigenic responses, and 3) the relative sensitivity of three mouse models of skin tumorigenesis; i.e. the genetically-initiated Tg.AC and RasH2 lines and the SENCAR mouse model. All three mouse models responded similarly, with mild inflammation and epidermal hyperplasia, to several weeks of treatment with a topical agent. Based on our previous research experience, we hypothesized that inflammation, irritation, proliferation, and/or hyperplasia in the skin would precede and predict the appearance of tumors in these sensitive mouse skin models. Consistent with our hypothesis, the test agent caused a low but significant tumorigenic response in Tg.AC mice. We propose that inflammation, irritation, and hyperplasia are sensitive predictors of a later tumorigenic response in Tg.AC mice. Further studies are needed, however, to better determine the relative sensitivity of these 3 models to a wider variety of agents.

Folate-targeted gene transfer in vivo.

Nonviral systemic delivery is one of the most attractive approaches for cancer gene therapy. To achieve this goal, various laboratories have developed cationic liposomes. However, when injected intravenously, cationic lipid-DNA complexes accumulate mostly into and transfect lung tissue. Here, we describe a method by which these complexes can be targeted to tumors using folic acid. Adding polyethylene glycol (PEG)-lipids to the complexes dramatically reduced both lung accumulation and gene transfer to lungs and tumors after intravenous administration. The presence of folic acid at the distal end of the PEG-lipid did not modify tumor accumulation of the complexes. However, with folate-targeted complexes, gene transfer activity was restored in tumors while the activity in lungs was reduced by 50- to 100-fold compared with nontargeted lipid-DNA complexes. This approach provides a first in vivo proof of concept to achieve targeted tumor gene delivery.