Hutchinson-Gilford progeria syndrome (HGPS) is a rare, genetic disorder characterized by a reminiscent of premature aging. Predominantly, HGPS caused by a de novo point mutation in the LMNA gene (c.1824C > T; p.G608G) that results in a toxic Lamin A variant called progerin. Progerin interferes with the lamin A function in a dominant-negative manner and exerts multiple toxic effects on cells, including nuclear abnormalities, genomic instability, and altered redox homeostasis. Children with the disease suffer from accelerated organ degeneration. Death results almost exclusively from coronary artery diseases or strokes at an average age of 14.6 years; currently, no cure exists for HGPS.

 

In this project, we propose to develop a mature vascular vessel via 3D bioprinting iPSC-derived HGPS endothelial (EC) and smooth muscle cells (SMCs) that can be manipulated in a perfusion-based bioreactor. We also implement an adenine base editor (ABE), a modified version of the CRISPR/Cas9 gene-editing system, to rescue the progeroid phenotype and functional properties of the HGPS vessel. Due to the inadequacy of animal models, there is a need to develop an improved 3D model to study disease mechanisms and to develop novel therapeutics. This collaboration will allow us to recapitulate the complexity of a native tissue via 3D printing and bioreactors. This system also has the obvious advantages of low cost, short experimental time, and translational potentials for developing novel therapeutics, and future high throughput drug screening.