Genetically Modified Mesenchymal Stem Cells for Decellularized Valve Prosthetics

University of Pittsburgh researchers have developed a novel approach to creating bioprosthetic heart valves (BHVs) that are more resistant to calcification. By genetically modifying mesenchymal stem cells (MSCs) to delete the telomerase (TERT) gene, these cells can be used to seed bioabsorbable scaffolds, which are then cultured in vitro and implanted into patients. This innovation aims to address the limitations of current BHVs, which are prone to calcification and eventual failure, by providing a more durable and effective solution for patients with calcific aortic valve disease (CAVD).

Alizarin red staining was used to show that aortic vascular smooth muscle cells (VSMCs) from wild type (WT) mice calcify after 21-28 days of osteogenic media, while VSMCs isolated from TERT knockout (TERTko) mice do not calcify. 

Description

The technology involves using CRISPR Cas9 gene editing tools to delete the telomerase gene in autologous mesenchymal stem cells. These genetically modified MSCs are then used to seed bioabsorbable scaffolds, which are cultured in vitro before being implanted into patients. The deletion of the telomerase gene reduces the expression of osteogenic genes and inhibits calcification, making the resulting bioprosthetic heart valves more resistant to calcification compared to current BHV replacements.

Applications

- Treatment of calcific aortic valve disease (CAVD)
- Development of durable bioprosthetic heart valves
- Tissue engineering and regenerative medicine

Advantages

This technology offers a novel approach to creating bioprosthetic heart valves. By genetically modifying mesenchymal stem cells to delete the telomerase gene, the resulting valves are less prone to calcification and have the potential to last longer than current BHV replacements. This approach leverages the use of CRISPR Cas9 gene editing tools and bioabsorbable scaffolds, providing a more effective and durable solution for patients with CAVD.

Invention Readiness

The technology is currently at the in vitro data stage. Researchers identified that the protein telomerase (TERT) is highly expressed in human mesenchymal stem cells that are calcifying, in CAVD valve tissues, and in valve interstitial cells isolated from patient CAVD valves. Experiments showed that knocking down TERT expression reduces the levels of the transcription factor RUNX2, a master regulator of osteogenesis. Genetic deletion of TERT in vascular smooth muscle cells was demonstrated to prevent calcification in vitro. The technology utilizes CRISPR Cas9 gene editing tools to delete the telomerase gene in autologous mesenchymal stem cells. These genetically modified MSCs are used to seed bioabsorbable scaffolds, which are then cultured in vitro.

IP Status

https://patents.google.com/patent/US11634716B2