The development of nucleic acids as therapeutics continues to gain significant attention as a promising opportunity for the treatment of many diseases given their ability to alter gene expression with a high degree of specificity. There are a multitude of candidates in clinical development, but they largely target diseases of the liver because of the bodys natural clearance of material to that organ. Indeed, the inability to deliver nucleic acids to multiple areas of the body has stymied their broad clinical development. Nucleic acid therapeutics may be especially efficacious for treating acute diseases given their ability to precisely modulate gene expression. One such disease is oral mucositis, a debilitating and treatment-altering side effect of chemotherapy and radiation. Given the acute nature of this disease, the capacity to deliver nucleic acid therapeutics locally in the oral cavity may prove prophylactic in preventing the onset of mucositis entirely. A technology enabling local administration of nucleic acids independent of formulation or sequence would prove invaluable for the treatment of a myriad of diseases outside of the liver, including oral mucositis. Suono Bios long-term goal is to develop therapeutic products leveraging our novel platform delivery technology that enables formulation and sequence- independent delivery of nucleic acids throughout the body to address a wide range of diseases with high-unmet need. The overall objective of this application, which is the next step toward attainment of our long-term goal, is to demonstrate the functional delivery in vivo of a broad range of unformulated nucleic acids using our lead clinical form-factor, the Suono 1, for local delivery in the oral cavity and to screen and identify in a preclinical model of oral mucositis a lead nucleic acid therapeutic for further clinical development. The rationale for this project is the use of low-frequency ultrasound technology to physically propel nucleic acids into tissue independent of formulation, achieving rapid, local delivery while enhancing bioavailability. In Aim 1, we will investigate the depth of penetration and define transfected cells following the delivery of two different naked mRNAs with different sequence lengths in vivo using the Suono 1. In Aim 2, we will build on this capacity by investigating the preclinical efficacy of different types of nucleic acids in combination with the Suono 1 in a hamster cheek model of oral mucositis. The proposed research is innovative as it utilizes low-frequency ultrasound to enable formulation- and sequence-independent delivery of a broad range of nucleic acids, obviating the need for tedious optimization of the therapeutic. Its successful completion will broadly demonstrate the capacity of the core technology to facilitate rapid, formulation-independent delivery of nucleic acid therapeutics and identify a lead nucleic acid therapeutic for further development for the treatment of oral mucositis.
Public Health Relevance Statement: PROJECT NARRATIVE Nucleic acid-based therapeutics hold tremendous promise for not only treating but potentially curing a myriad of diseases with high unmet need; however, delivery of nucleic acids remains a significant challenge to their use clinically. This proposal aims to develop a platform delivery system capable of ultra-rapid delivery of nucleic acids independent of formulation or sequence and apply this technology for the treatment of oral mucositis, a debilitating disease. This technology will impact clinical practice by expediting the translation of these therapies to the clinic, reducing the need for tedious formulation development.
NIH Spending Category: Bioengineering; Biotechnology; Dental/Oral and Craniofacial Disease; Digestive Diseases; Gene Therapy; Genetics
Project Terms: Acute; Acute Disease; Address; Antisense Oligonucleotides; Area; Attention; Attenuated; base; Biological Availability; Cell membrane; cell type; Cells; Cheek structure; Chemicals; chemotherapy; Clinic; Clinical; clinical application; clinical development; clinical practice; Colon; Data; Development; Devices; Disease; Encapsulated; FDA approved; Formulation; Frequencies; gastrointestinal; Gene Expression; Genes; Goals; Hamsters; in vivo; Individual; Inflammation; Inflammatory; Injury; innovation; Investigational New Drug Application; Lead; Length; Lesion; Liquid substance; Liver; Liver diseases; MADH7 gene; Messenger RNA; Methods; Modeling; Mucositis; Mucous Membrane; Nature; new technology; novel; nucleic acid delivery; nucleic acid-based therapeutics; Nucleic Acids; Oligonucleotides; Oral; Oral cavity; oral mucositis; Oral mucous membrane structure; Organ; Outcome; Patients; Penetration; Phase; pre-clinical; Pre-Clinical Model; preclinical efficacy; preclinical safety; prevent; prophylactic; Radiation; Reporter Genes; Research; side effect; Small Business Innovation Research Grant; Small Interfering RNA; Specificity; Surface; Syringes; System; Technology; Testing; Therapeutic; therapeutic target; therapy development; Tissues; Translations; Ultrasonography; Work
