This STTR Phase I proposal details the rationale and the research plan for the development of a novel liquid embolizing agent composed of the genetically engineered protein polymer, SELP (silk-elastinlike protein)-815K, to embolize cerebral aneurysms. The SELP embolic would reduce the risk of aneurysm rupture while minimizing the risk of recanalization after treatment and providing a platform for delivering newly developed drugs or cell therapies directly to the aneurysmal sac. This work will result in an embolic that can potentially improve aneurysm healing, deliver therapeutics locally, and reduce the risks associated with the embolization of cerebral arteries.
Public Health Relevance Statement: SUMMARY This STTR Phase I proposal addresses the significant need for improved options to treat cerebral aneurysms. Cerebral aneurysms are prone to rupture, resulting in hemorrhagic stroke, crippling paralysis, or even death. Physicians treat cerebral aneurysms by blocking blood flow to the aneurysmal sac via surgical sealing or filling the sac with radiopaque embolic materials under fluoroscopic guidance from a microcatheter. Current mechanical embolic agents, such as injectable coils, depend upon inducing thrombus to stop blood from accessing the aneurismal sack, leading to increased risk of recanalization and subsequent rupture. Clinically available liquid embolic agents are able to completely fill the aneurysmal sac, but use toxic organic solvents or produce inflammatory by-products that potentially lead to chronic inflammatory disease, vasospasm, and angionecrosis. For this project we will create a liquid embolic agent that fills aneurysms, reinforces the weakened vasculature, and facilitates healing. This proposal utilizes silk-elastinlike protein polymers (SELP) that combine the solubility of mammalian elastin and the strength of silk to create molecules with tunable solubility and mechanical properties. We hypothesize that a non-toxic radiopaque liquid embolic hydrogel will improve the rate of healing and reduce the risk of aneurysm rupture compared to current metal coil or polyvinyl alcohol based embolics. Building on our expertise in the fields of recombinant polymer design and local drug delivery, we will pursue the following three aims: (1) synthesize and characterize radiopaque SELP formulations to transition from an injectable liquid to a solid hydrogel; (2) evaluate delivery and stability of radiopaque SELP formulation in an in vitro aneurysm model, and (3) analyze performance SELP embolics in vivo in a rabbit aneurysm model.
Project Terms: Address; Aftercare; Aneurysm; aqueous; Arteriovenous malformation; base; Biocompatible Materials; Biological Response Modifier Therapy; biomaterial compatibility; Blood; Blood flow; Brain hemorrhage; Catheters; Cell Therapy; Cells; Cerebral Aneurysm; cerebral artery; Cerebrovascular system; Cessation of life; Characteristics; Chronic; Clinical; cost; cytotoxicity; design; Development; Development Plans; Disease; Elastases; Elastin; Exposure to; Foreign Bodies; Formulation; Fracture; Functional disorder; Gel; Genetic; Genetic Engineering; healing; hemodynamics; Human; Hydrogels; Hypervascular; improved; In Vitro; in vivo; in vivo Model; Inflammatory; Injectable; Injection of therapeutic agent; insight; Instruction; iodixanol; Label; Lead; Liquid substance; local drug delivery; mechanical properties; Mechanics; Medical; metallicity; Metals; Modeling; Molecular Weight; Monitor; monomer; Neck; Nervous System Trauma; Neurologic Symptoms; next generation; novel; Operative Surgical Procedures; Organic solvent product; Oryctolagus cuniculus; Paralysed; Performance; Peripheral; Pharmacotherapy; Phase; Physicians; Polymers; Polyvinyl Alcohol; Preparation; pressure; prevent; Protein Engineering; Proteins; Recombinant Proteins; Recombinants; Research; response; Risk; risk minimization; Rupture; Ruptured Aneurysm; seal; Silk; Small Business Technology Transfer Research; soft tissue; Solid; Solubility; standard of care; Structure; Symptoms; System; Testing; Therapeutic; Therapeutic Embolization; Thrombus; Tissues; Translating; Treatment Protocols; tumor; Vasculitis; Vasospasm; Wages; Work
