Tau Protein Aggregation Inhibitors for Tauopathies

DESCRIPTION (provided by applicant): Transcatheter aortic valve implantation (TAVI) is a minimally invasive approach to valve replacement that has had a rapid and profound clinical impact. Less than ten years after the first human use of a TAVI device, nearly 20,000 patients annually receive these novel devices. Today, this clinical population is limited to older, sicker patients who cannot tolerate an open surgical procedure. While commercially available TAVI devices demonstrate excellent survival rates, the large size of these 'first generation' devices drives a high rate (20- 30%) of serious complications. Accordingly, the primary design objective for improved second generation devices is a reduction in device diameter. The majority of the crossing profile (diameter) comes from the cusps themselves, which are comprised of relatively thick pericardium derived from animal sources. Thus a reduction in cusp thickness would have a dramatic impact on patient outcomes (decreased stroke and access complications).Moreover, as complication rates are decreased, it is clear that TAVI use will broaden beyond the inoperable patient population to include younger, healthier patients who would benefit from a less invasive procedure. Expanded use of TAVI devices will also have a positive economic impact on the healthcare system, with decreased O.R. times, shorter hospital stays, and reduced complication rates. We have developed a technology called 'Tissue Engineering by Self-Assembly' (TESA), where robust, tissue constructscan be built from cell-synthesized sheets and/or threads, without any biomaterials or chemical fixation that can trigger degradation, calcification, or inflammation. The mechanical properties of TESA valve cusps can also be changed regionally, using folding, layering, or embedding strategies. The overarching goal of this SBIR Phase I proposal is to demonstrate the feasibility of using the TESA platform to build a functional TAVI valve with a delivery profile ~25% smaller than current commercial devices. InSpecific Aim #1, we will quantify the mechanical properties (ultimate tensile strength, Young's modulus, bending stiffness and suture holding strength) of several different TESA configurations. This will include characterizing the properties of sheets ofvarious thicknesses and sheets that are reinforced by different folding or embedding strategies. In total, we will test 17 different configurations including pericardium and native valve controls. We will then draw from this 'library' of mechanical properties to guide tissue design in both the suture zone (prioritizing suture holding strength) and the coaptation zone where the individual cusps come together (prioritizing strength then flexibility). In Specific Aim #2, we will build and test these novel TAVI devices for basic functionality and resistance to dynamic fatigue. If success criteria are not met (deploy without perforation, withstand 1k cycles in a hemodynamic tester and 5M cycles in an accelerated wear tester), we will revise the valve cusp design based on the observed failure mode and the data 'library' produced in Aim #1. If these functional milestones are met, animal testing will be pursued in a Phase II application. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Over the last 3 years, transcatheter aortic valve implantation (TAVI) has had a profound impact on the health and survival of patients too weak to withstand open, surgical valve replacement. First generation TAVI devices are still extremely bulky, and the vast majority ofserious complications are directly related to the diameter of the device. In this SBIR Phase I proposal, we describe an approach to reduce the overall crossing profile of TAVI devices, which would reduce complication rates and increase the number of patients eligible for this life-saving, cost-effective therapy.