Selective inhibition of CYP26A1 in the skin for the treatment of ichthyosis

Project Summary Abstract DermaXon s project goal is to develop efficacious novel selective inhibitors of CYP A for the topical treatment of ichthyosis Congenital ichthyosis is a family of hereditary disorders of keratinization characterized by dry scaling skin that may be thickened or very thin impacting the quality of life of patients and their family members Currently there is no cure for ichthyosis and available medicines are aimed only at moisturizing and exfoliating to reduce dryness scaling and cracking of skin Retinoic acid RA derivatives are known to normalize abnormal differentiation of keratinocytes and have keratolytic effects that mitigate hyperkeratosis in patients with ichthyosis However RA has poor pharmacokinetics in humans because it induces its own clearance by upregulating metabolic enzymes and its use is limited due to mucocutaneous side effects abnormalities of serum lipid profiles bone spurs and hair loss The clearance of RA is predominantly mediated by cytochrome P family enzymes CYP of which there are three isoforms CYP A CYP B and CYP C For the first time DermaXon has shown that CYP A is the isoform responsible for RA metabolism in human skin Currently approved topical RAR selective retinoids whose effects are mediated by direct receptors activation are also potent non selective inhibitors of both CYP A and B which likely explains their adverse side effects including retinoid dermatitis In this STTR DermaXon will demonstrate that selective inhibition of CYP A will increase RA concentration in ichthyotic skin resulting in normalization of keratinocyte differentiation and mitigating hyperkeratosis associated with ichthyosis This approach will provide a therapeutic advantage in ichthyosis without side effects associated with non specific inhibition of other CYP s We are the only group world wide to have developed selective nanomolar CYP A inhibitors providing a new therapeutic class against ichthyosis These inhibitors shown to be highly selective for CYP A avoid the adverse effects induced by non targeted P inhibition associated with previously described non specific azole containing CYP inhibitors such as liarozole We are uniquely suited to demonstrate the utility of CYP A as a therapeutic target as we bring together the expertise of academic industry partnerships between DermaXon expert in drug discovery and formulation and Northwestern University Dr Paller expert in ichthyosis In this proposed award period DermaXon will complete the characterization of the previously developed lead candidate structures which are highly potent and selective CYP A inhibitors The effects of these CYP A inhibitors will be assessed and compared to the effects of a dual CYP A B inhibitor and a selective CYP B inhibitor at increasing RA concentration in keratinocytes isolated from patients with ichthyosis and in a human epidermis model of ichthyosis By the end of this project DermaXon will have identified a potent selective topically active safe and efficacious CYP inhibitor that can treat keratinization disorders in preclinical skin models of ichthyosis and ready for IND enabling formal studies to address the therapeutic needs in ichthyosis PROJECT NARRATIVE Public Health Relevance Ichthyosis is a family of rare and neglected genetic disorders characterized by persistently dry rough and scaly skin Current treatment options do not adequately address patient needs presenting significant efficacy or tolerability concerns DermaXon has recently identified a new series of selective CYP A inhibitors acting through retinoic acid metabolism inhibition in the skin as novel class of therapeutic agents for the topical treatment of hyperkeratosis associated with ichthyosis This STTR Phase will generate data necessary to validate our proposed target CYP A for the treatment of cornification disorders and to develop the most promising selective CYP A inhibitor as a new approach to treating ichthyosis topically