Turning mechanisms of heart development into remedial therapies for heart valvuloseptal defects

Project: Research

Investigators

  • Roger Markwald (PI)

Description

Structural heart birth defects that are immediately recognizable at birth and requiring clinical intervention and management frequently are the result of errors in morphogenetic remodeling. However, remodeling errors can also be more subtle, predisposing what initially appear to be 'normal' valves at birth into ones that progressively undergo degenerative changes in tissue organization that, over time, compromise biomechanical properties potentially leading to prolapse, calcification, regurgitation, arrhythmias, heart failure and even death. To benefit patients born with developmentally-linked, adverse remodeling defects, the primary goal of this Transformative proposal is explore whether basic discoveries made over the past three decades on the mechanisms that regulate normal healthy valve remodeling can be turned into in vivo remedial therapies for valve defects or functional deficits. Because, the shape-defining, remodeling steps required for tissue assembly and organization into mature valve leaflets are not completed until after birth, there is an accessible open window for genetic intervention if a way can be found to deliver them in vivo. As a starting point, we propose to use the periostin null mouse model as a prototype for testing the hypothesis that periostin and filamin-A function as a central regulatory axis in normal valvuloseptal morphogenesis that can be utilized to initiate and sustain remediation of heart valve and septal defects. Advantages of the periostin null model is that it is not lethal, defects have high penetrance, its phenotype is well characterized as are its signaling pathways and, in tissue culture, periostin null valve progenitor cells respond to the gene delivery approaches to be used in vivo in this study. Two strategies (each a specific aim) are proposed to convey remedial gene vectors that express periostin or one of its downstream signaling targets to null valve leaflets and atrial septa. These are 1) a cell-based approach in which a subpopulation of circulating CD45+ cells that normally track to the heart after birth and homeostatically engraft into valve leaflets and associated septa and (2) a lineage specific dual nanoparticle gene (plasmid) delivery system in which most, if not all cells in the body take up the nanoparticles but only those in a specific lineage can activate them. Preliminary data indicate the potential feasibility of these approaches: after 3 weeks of neonatal injections, various combinations of the
Award amount$300,000.00
Award date07/01/2019
Program typeTransformational Project Award
Award ID19TPA34900016
Effective start/end date07/01/201906/30/2022
StatusActive