We request NIH support to develop heparin-binding epidermal growth factor-like growth factor (HB-EGF) as treatments for oral aphthous ulcer disease: Chronic recurrent oral aphthous ulcers are the most common type of inflammatory condition of the oral mucosa with a prevalence of 2% to 10% in Caucasian populations. They can be a manifestation of trauma or a systemic inflammatory process or often they are truly idiopathic. They can cause severe pain and have the potential to limit oral intake of fluids. The standard of care currently is symptomatic treatment involving dietary changes and topical anti-inflammatories, antiseptics, or anesthesia. In severe cases, systemic immunomodulatory agents are used. Currently, there is no epithelization agent available that would address the histological problem. For this project, we will leverage the combined expertise of the Santa Maria Lab, which developed HB-EGF for topical administration in the oral cavity, with Auration Biotech, who have already successfully preclinically translated the same biologic to clinical trials for another indication. Our innovative approach aims to be the first available to accelerate aphthous ulcer wound healing that directly addresses the epithelium. We have shown that locally administered HB-EGF accelerates and thickens epithelialization and makes the neo epithelial layer more adherent to the underlying wound. Therefore, we hypothesize that this is likely to improve aphthous ulcer wound healing in a tongue surgical ulcer mouse model. Our aims are focused on optimizing our current treatment for this new indication and then confirming efficacy in a relevant in vivo model. Our Aims encompass: (1) optimizing the microgel delivery for tongue ulcers so that it can be applied to a more focused area of the oral cavity and (2) confirming the ability of the HB-EGF delivered by mucoadhesive microgels to improve tongue ulcer wound healing in our animal model. Our outcomes will be to show reduced epithelial separation and wound reopening, greater epithelial thickness, and earlier wound closure in HB-EGF treated tongue ulcers. If the outcomes of this Phase I project are reached, we will apply for Phase II funding to further commercial development. Ultimately, if successful, patients with aphthous ulcers achieve significantly reduced pain and avoid dehydration with the potential to significantly improve quality of life in these patients. Public Health Relevance Statement Project Narrative Chronic recurrent oral aphthous ulcers, the most common type of inflammatory condition of the oral mucosa with a prevalence of 2% to 10% in Caucasian populations, can be a manifestation of trauma or systemic inflammatory process or are truly idiopathic, and no effective medical therapies have been identified to date that shorten the disease. We have shown that locally administered heparin-binding epidermal growth factor-like growth factor (HB-EGF) accelerates and thickens epithelialization and makes the neo epithelial layer more adherent to the underlying wound and therefore is likely to improve aphthous ulcer wound healing. In this research project we aim to develop an effective treatment by combining HB-EGF delivered by mucoadhesive microgels and showing efficacy in a mouse model.
Project Terms: Anesthesia procedures ; Anesthesia ; Local Anti-Infective Agents ; Antiseptics ; Local Antiinfective Agents ; Topical Anti-Infective Agents ; Topical Antiinfective Agents ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Beds ; Biomedical Engineering ; bio-engineered ; bio-engineers ; bioengineering ; Biotechnology ; Biotech ; Clinical Trials ; Combined Modality Therapy ; Multimodal Therapy ; Multimodal Treatment ; combination therapy ; combined modality treatment ; combined treatment ; multi-modal therapy ; multi-modal treatment ; Contracture ; Cytoplasmic Granules ; granule ; Dehydration ; body water dehydration ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Ear ; Family ; Gel ; Goals ; Human ; Modern Man ; In Vitro ; Lidocaine ; Lignocaine ; Oral mucous membrane structure ; Buccal Mucosa ; Mouth Mucosa ; Oral Mucosa ; oral mucosae ; oral mucosal ; Mouthwash ; Mus ; Mice ; Mice Mammals ; Murine ; Muscle ; Muscle Tissue ; muscular ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Pain ; Painful ; Patients ; Drug Kinetics ; Pharmacokinetics ; Play ; Publishing ; Quality of life ; QOL ; Epidermal Growth Factor Receptor ; EGF Receptor ; EGFR ; ERBB Protein ; Epidermal Growth Factor Receptor Kinase ; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase ; Epidermal Growth Factor-Urogastrone Receptors ; HER1 ; TGF-alpha Receptor ; Transforming Growth Factor alpha Receptor ; Urogastrone Receptor ; c-erbB-1 ; c-erbB-1 Protein ; erbB-1 ; erbB-1 Proto-Oncogene Protein ; erbBl ; proto-oncogene protein c-erbB-1 ; Recurrence ; Recurrent ; Natural regeneration ; Regeneration ; regenerate ; Rodent ; Rodentia ; Rodents Mammals ; Role ; social role ; Safety ; skin ulcer ; ulcerative wounds ; Aphthous Stomatitis ; Aphthae ; Aphthous Ulcer ; Canker Sore ; Time ; Tissues ; Body Tissues ; Tongue ; Translating ; Translations ; Ulcer ; Ulceration ; Caucasians ; Caucasian ; Caucasian Race ; Caucasoid ; Caucasoid Race ; Occidental ; white race ; wound healing ; Wound Repair ; wound resolution ; heparin-binding EGF-like growth factor ; improved ; Site ; Area ; Chronic ; Encapsulated ; Phase ; Biological ; Histologic ; Histologically ; Medical ; Epithelial ; Oral cavity ; Buccal Cavity ; Buccal Cavity Head and Neck ; Cavitas Oris ; Mouth ; Epidermal Growth Factor ; Anthelone U ; Epidermal Growth Factor-Urogastrone ; Urogastrone ; beta-Urogastrone ; ERBB2 gene ; ERBB2 ; HER -2 ; HER-2 ; HER2 ; HER2 Genes ; HER2/neu ; NEU Oncogene ; NEU protein ; Oncogene ErbB2 ; TKR1 ; c-erbB-2 ; c-erbB-2 Genes ; c-erbB-2 Proto-Oncogenes ; erbB-2 Genes ; herstatin ; neu Genes ; Funding ; Research Project Grants ; R-Series Research Projects ; R01 Mechanism ; R01 Program ; Research Grants ; Research Projects ; Collaborations ; fluid ; liquid ; Liquid substance ; Surgical wound ; Inflammatory ; Deposit ; Deposition ; Scientist ; Oral ; System ; Operative Procedures ; Surgical ; Surgical Interventions ; Surgical Procedure ; surgery ; Operative Surgical Procedures ; success ; bioresorbable polymer ; degradable polymer ; biodegradable polymer ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; release factor ; novel ; member ; 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 ; Touch ; tactile sensation ; Touch sensation ; EGF Receptor 3 Gene ; ERBB3 ; HER3 ; ERBB3 gene ; ErbB-4 ; ErbB4 ; HER-4 ; HER4 ; NDF/Heregulin Receptor Gene ; ErbB4 gene ; Radiation ; Modeling ; Property ; drug development ; heparin bound ; Heparin Binding ; Molecular Interaction ; Binding ; Thickness ; Thick ; preventing ; prevent ; Address ; Dose ; Data ; Intake ; Resolution ; in vivo ; in vivo Model ; Process ; 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 ; oral mucositis ; oromucositis ; pre-clinical ; preclinical ; neovascularization ; oral condition ; healing ; Outcome ; wound ; tissue wound ; wounding ; wounds ; Population ; Prevalence ; Trauma ; innovation ; innovate ; innovative ; mouse model ; murine model ; commercialization ; standard of care ; effective therapy ; effective treatment ; efficacy testing ; Formulation ; symptom treatment ; symptomatic treatment ; treat symptom ; associated symptom ; co-morbid symptom ; co-occuring symptom ; comorbid symptom ; concurrent symptom ; cooccuring symptom ; symptom association ; symptom comorbidity ; Growth Factor ; Growth Agents ; Growth Substances ; Proteins Growth Factors ; wound closure ; pain reduction ; reduce pain ; epithelial wound ; dietary ;
