Animal models of disease are transforming preclinical research, allowing critical insights into disease mechanisms and evaluation of new therapeutics. While the utility and availability of animal models in research is swiftly expanding often the research tools necessary to optimally exploit these models are available only to the small group of individuals that developed them. Although NIH policies encourage sharing of data and tools generated using NIH-funding, the significant investments necessary to improve and disseminate research tools often limit the sharing of these innovative tools. The development of neurological and mental health drugs requires preclinical testing in multiple animal models to demonstrate efficacy and safety and to elucidate corresponding mechanistic details of therapeutic action. Drug delivery to the central nervous system (CNS) to target neurological diseases is particularly problematic because the blood-brain barrier (BBB) prevents most compounds from crossing into the brain from the blood. Although direct intracerebral ventricle (ICV) injection is widely used, it is inefficient and may interfere with pharmacodynamic evaluation in animal models of disease. Additionally, the delivery of large biological molecules such as protein therapeutics or antibodies is complicated by uncertain distribution throughout the brain after ICV. While other methods of animal CNS delivery exist, these methods are not precise or require complex surgery. Thus, the difficulty of distributing drugs to the central nervous system severely limits drug development efforts in preclinical animal models. Our novel pressurized olfactory delivery (POD) device allows non-invasive, targeted delivery of drugs and biologics to the CNS using the nose-to-brain route of the olfactory region to bypass the BBB. The POD device is ideal for preclinical animal studies because it precisely targets the central nervous system without disrupting the BBB and is scalable for use across a spectrum of animal models. Refinement of our bench-use POD animal devices for wide-spread preclinical research use will require several stages. First, we will develop machined prototypes of the POD devices and verify that they are comparable to the bench-use versions. Once verified, we will develop and verify molded prototypes of each machined POD device. Finally, we will validate the molded prototypes and associated in vitro testing methodologies via an extensive battery of tests to ensure they meet or exceed specifications for manufacturing. The animal POD devices, if commercialized, would benefit neurological and mental health disease researchers by making preclinical animal studies more efficient and clarifying the effects of the therapeutic versus the effects of the delivery intervention.
Public Health Relevance Statement: Public Health Relevance: Animal models of disease are transforming neurological and mental health research, allowing advances in understanding disease mechanisms and in developing new drugs for treatment. This project involves development of an innovative research tool to deliver drugs to the brains of animals used in research to help develop new drugs for humans. Development of this device will allow less invasive drug delivery in research animals (including mice, rats, rabbits, dogs, and primates), making animal research more efficient and clarifying the effects of the therapeutic versus the effects of the delivery intervention.
Project Terms: Animal Disease Models; Animal Experimentation; Animal Model; Animals; Antibodies; Biological; Blood; Blood - brain barrier anatomy; Brain; Bypass; Canis familiaris; Central Nervous System Agents; Characteristics; commercialization; Complex; Computer-Aided Design; Deposition; Development; Device or Instrument Development; Devices; Disease; Dose; drug candidate; Drug Delivery Systems; drug development; Ensure; ergonomics; Evaluation; Funding; Human; improved; In Vitro; in vitro testing; Individual; Injection of therapeutic agent; innovation; insight; Intervention; Investments; Liquid substance; Marketing; meetings; Mental Health; Methodology; Methods; Modeling; Molds; Mus; nervous system disorder; Neuraxis; Neurologic; Nose; novel; novel therapeutics; Operative Surgical Procedures; Oryctolagus cuniculus; Pharmaceutical Preparations; Pharmacodynamics; Policies; Powder dose form; pre-clinical; pre-clinical research; Preclinical Testing; prevent; Primates; prototype; public health relevance; Quality Control; Rattus; Research; Research Personnel; Residual state; Route; Safety; sharing data; Staging; targeted delivery; Testing; Therapeutic; Therapeutic Effect; therapeutic protein; tool; United States National Institutes of Health; Validation
