RESUMEN
BACKGROUNDHyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans.METHODSWe conducted an open-label, single-center, dose-response study of hymecromone in healthy adults. Subjects received hymecromone at 1200 (n = 8), 2400 (n = 9), or 3600 (n = 9) mg/d divided into 3 doses daily, administered orally for 4 days. We assessed safety and tolerability of hymecromone and analyzed HA, 4-MU, and 4-methylumbelliferyl glucuronide (4-MUG; the main metabolite of 4-MU) concentrations in sputum and serum.RESULTSHymecromone was well tolerated up to doses of 3600 mg/d. Both sputum and serum drug concentrations increased in a dose-dependent manner, indicating that higher doses lead to greater exposures. Across all dose arms combined, we observed a significant decrease in sputum HA from baseline after 4 days of treatment. We also observed a decrease in serum HA. Additionally, higher baseline sputum HA levels were associated with a greater decrease in sputum HA.CONCLUSIONAfter 4 days of exposure to oral hymecromone, healthy human subjects experienced a significant reduction in sputum HA levels, indicating this oral therapy may have potential in pulmonary diseases where HA is implicated in pathogenesis.TRIAL REGISTRATIONClinicalTrials.gov NCT02780752.FUNDINGStanford Medicine Catalyst, Stanford SPARK, Stanford Innovative Medicines Accelerator program, NIH training grants 5T32AI052073-14 and T32HL129970.
Asunto(s)
Ácido Hialurónico , Himecromona , Administración Oral , COVID-19 , Europa (Continente) , Matriz Extracelular/metabolismo , Humanos , Ácido Hialurónico/metabolismo , Himecromona/administración & dosificación , Himecromona/efectos adversosAsunto(s)
Desensibilización Inmunológica/métodos , Hipersensibilidad al Cacahuete/terapia , Academias e Institutos , Administración Oral , Comités Consultivos , Regulación Gubernamental , Humanos , Hipersensibilidad al Cacahuete/inmunología , Formulación de Políticas , Estados Unidos , United States Food and Drug AdministrationRESUMEN
With the rising prevalence, food allergies have become a significant health burden that affects 6% to 13% of the global population. Although oral immunotherapy (OIT) has been promising for food allergies, this therapy has limitations, including high rates of adverse reactions and long treatment periods. Biologics may address these limitations by increasing the safety and tolerability of OIT and decreasing treatment periods. The use of biologics and vaccines are actively being explored as monotherapy as well as adjunctive therapy in combination with allergen specific OIT. A number of biologics that target key molecules known to be involved in food allergy are under investigation, including anti-immunoglobulin E therapy (omalizumab), anti-interleukin (IL) 4 receptor a (dupilumab), anti-IL-5 (mepolizumab and reslizumab), and anti-IL-5R (benralizumab), anti-IL-33 (etokimab), and peanut DNA plasmid vaccines. In the era of precision medicine, the future of food allergy looks promising, and biologics will provide treatment as well as further insights into the molecular mechanisms associated with food allergy.