Onychomycosis is an extremely common and difficult-to-treat fungal nail infection that causes nail disfigurement, pain, associated infections, and psychosocial effects that negatively impact quality of life. It is caused predominantly by dermatophytes such as Trichophyton rubrum (T. rubrum) but may also involve yeasts such as Candida albicans or non-dermatophyte molds. Typical risk factors include trauma, aging, and history of tinea pedis, but additional comorbidities such as diabetes, obesity, and immune suppression are also significant risk factors, which are increasing in prevalence. Onychomycosis is typically treated by antifungal drugs administered topically or systemically, but each approach has significant shortcomings leading to low complete cure rates of less than 30% and 60%, respectively5,6. Topical antifungals are limited by difficulties in delivering the drug through the nail plate, which is a highly keratinized, difficult-to-penetrate protective barrier3,4. Systemic antifungals are generally high cost, may be restricted by limited vascular access to the site of infection, and are associated with potentially severe adverse effects, including hepatotoxicity. In addition, drug resistance in onychomycosis may manifest through the development of biofilm growth or through induction of efflux pumps and mutations. Therefore, the development of an improved treatment for onychomycosis would fill a significant unmet need and improve the quality of life for those affected by the disease. The goal of this proposal will be achieved through two interconnected specific aims. In Specific Aim 1, zMPNO for clinical translation will be synthesized and characterized prior to being evaluated for in vitro antifungal activity against T. rubrum and other fungal strains relevant to onychomycosis as well as for preliminary cytotoxicity. In Specific Aim 2, the concentrations of zMPNO in a representative cream vehicle required to deliver sufficient NO through the nail plate to achieve fungicidal activity will be established. This formulation will then be used to assess zMPNO efficacy in treating T. rubrum and C. albicans in a RoMar™ ex vivo infected nail model (MedPharm). At the conclusion of this Phase I study, an Optimized Formulation will be established with defined concentration of zMPNO suitable for further formulation development, scale-up, safety studies, and ex vivo efficacy studies in Phase II.
Public Health Relevance Statement: Onychomycosis is the most common fungal nail infection worldwide; it causes nail disfigurement, pain, and negative psychosocial effects and is uniquely challenging to treat due to difficulties in delivering appropriate antifungal medications to the site of infection. The goal of this proposal is to develop a novel therapeutic for treating onychomycosis: specifically, a topically applied microparticle formulation that delivers nitric oxide with enhanced nail penetration and potent antifungal activity. An optimized formulation will be tested in an in vitro infected nail model against the fungal pathogens T. rubrum and C. albicans.
Project Terms: Affect; Aging; Antifungal Agents; Antifungal Drug; Therapeutic Fungicides; anti-fungal; anti-fungal agents; anti-fungal drug; antifungals; Aspergillus flavus; Biological Assay; Assay; Bioassay; Biologic Assays; Blood Vessels; vascular; Cadaver; Candida; Monilia; Candida albicans; C albicans; C. albicans; C.albicans; comorbidity; co-morbid; co-morbidity; Arthrodermataceae; Cutaneous Fungus; Dermatomyces; Dermatophytes; Diabetes Mellitus; diabetes; Disease; Disorder; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Fibroblasts; Gases; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Recording of previous events; History; Human; Modern Man; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; In Vitro; Infection; keratinization; cornification; keratinocyte; Lead; Pb element; heavy metal Pb; heavy metal lead; Medicine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Nails; Nail plate; Endogenous Nitrate Vasodilator; Endothelium-Derived Nitric Oxide; Mononitrogen Monoxide; Nitrogen Monoxide; Nitrogen Protoxide; endothelial cell derived relaxing factor; Nitric Oxide; adiposity; corpulence; Obesity; living system; Organism; Painful; Pain; Particle Size; QOL; Quality of life; Risk Factors; Safety; Cristobalite; Sand; Silica; Tridymite; Silicon Dioxide; Testing; Athlete's Foot; Tinea Pedis; Tinea Unguium; Onychomycosis; Tissues; Body Tissues; Trichophyton; Endodermophyton; Trychophyton; Yeasts; Generations; Measures; Microbial Biofilms; biofilm; Diatoms; Bacillariophyta; base; improved; Site; Clinical; Penetration; Phase; Dermal; Hepatotoxic effect; Liver Toxicity; Toxic effect on liver cells; hepatic toxicity; hepatoxicity; Hepatotoxicity; Human Figure; Human body; Antibacterial Agents; anti-bacterial; antibacterial; Anti-Bacterial Agents; Therapeutic; Morphology; Filamentous Fungi; Molds; Industrial Fungicides; fungicidal; fungicide; Industrial fungicide; Scientist; Minimum Inhibitory Concentrations; Minimum Inhibitory Concentration measurement; System; collegiate; college; Lytotoxicity; cytotoxicity; novel; Topical Drug Administration; administer topically; apply topically; deliver topically; topical administration; topical delivery; topical drug application; topical treatment; topically administered; topically applied; topically delivered; topically treated; treat topically; Topical application; Modeling; Adverse effects; Bacterial Antibiotic Resistance; antibiotic resistant bacteria; bacterial antibiotic resistant; bacterial resistance to antibiotic; Cream; Address; Dose; Psychosocial Effect; Treatment/Psychosocial Effects; Development; developmental; Immunomodulators; IMiD; Immune modulatory therapeutic; immune modulating agents; immune modulating drug; immune modulating therapeutics; immune modulators; immune modulatory agents; immune modulatory drugs; immunomodulating agents; immunomodulatory agents; immunomodulatory drugs; immunomodulatory therapeutics; safety study; cost; scale up; Prevalence; Trauma; efflux pump; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; prototype; chronic rhinosinusitis; phase 1 study; Phase I Study; Formulation; efficacy study; clinical translation; manufacturability; pathogenic fungus; fungal pathogen; fungi pathogen
