Induced differentiation and maturation of stem cells via interruption of DNA replication

Unmet Need: Effective stem cell differentiation for research and clinical applications

Differentiation of pluripotent stem cells into various cell types has the potential to provide a wide range of therapeutic and investigational applications, including cell replacement therapies, tissue engineering, and drug screening. For example, Type I Diabetes patients are dependent on exogenous insulin due to their lack of beta cells; therefore, the ability to re-introduce functional beta cells via cell replacement therapy can greatly improve their condition. Current methods to produce terminally differentiated, functional cells rely on the modulation of extrinsic signaling pathways and the stem cell niche microenvironment. However, a robust pipeline capable of accurately and efficiently differentiating stem cells into distinct, functional cell types is not yet available.

The Technology: Blocking DNA replication to generate mature stem cells

This technology describes methods to terminally differentiate stem cells by interfering with the cell’s ability to undergo DNA replication using various cell cycle inhibitors. These inhibitors target a variety of enzymes important to DNA replication, including, but not limited to, DNA polymerase, cell cycle transcription factors, topoisomerase, and helicase. These interventions induce cell cycle exit, which drives subsequent terminal differentiation and functional maturation of the cell. This technology may be used to robustly differentiate stem cells into a variety of cell types, such as mature pancreatic beta cells, neurons, and muscle cells, for research, drug testing, and therapeutic use.

This technology has been validated with human pluripotent stem cells.

Applications:

Terminal differentiation of stem cells into a variety of fully functional cell types
Terminal differentiation of stem cells into mature pancreatic beta cells for patient-derived diabetes therapies
In vitro cell assays
Drug screening
Cell transplantation
Interruption of DNA replication
Tissue engineering for organ transplants

Advantages:

Capable of generating various mature and functional cell types robustly
Can be conducted with multiple types of DNA replication inhibitors/agents
Provides a potential method for treating type I diabetes
Applicable to various disease models
Robust terminal differentiation

Lead Inventor:

Dietrich Egli, Ph.D.

Patent Information:

Patent Pending(US20210052665)

Related Publications:

Sui L, Xin Y, Georgieva D, Diedenhofen G, Haataja L, Su Q, Wang Y, Zuccaro M, Kim J, Fu J, Xing Y, Baum D, Goland RS, Oberholzer J, Barbetti F, Arvan P, Kleiner S, Egli D. “Establishing cell-intrinsic limitations in cell cycle progression controls graft growth and promotes differentiation of pancreatic endocrine cells.” bioRxiv. 2020 Mar 14.

Tech Ventures Reference:

IR CU18295, CU19085
Licensing Contact: Kristin Neuman

Capable of generating various mature and functional cell types robustly
Can be conducted with multiple types of DNA replication inhibitors/agents
Provides a potential method for treating type I diabetes
Applicable to various disease models
Robust terminal differentiation