In vivo hematopoietic stem cell modification by mRNA delivery

Area of Science:

• Hematology
• Gene Therapy
• Nanomedicine

Background:

• Hematopoietic stem cells (HSCs) are crucial for lifelong blood cell production.
• Hematopoietic stem cell transplantation (HSCT) is used to replace diseased HSCs but has significant side effects and limited accessibility.
• Current HSCT conditioning methods are often genotoxic and invasive.

Purpose of the Study:

• To develop a novel targeted delivery system for HSCs.
• To enable in vivo gene editing and nongenotoxic conditioning for HSCT.
• To explore a potential cure for genetic blood disorders by modifying HSCs directly.

Main Methods:

• Development of CD117/LNP-mRNA, a lipid nanoparticle (LNP) encapsulating mRNA and targeted to the CD117 receptor on HSCs.
• In vivo delivery of an anti-human CD117/LNP-based editing system.
• In vivo delivery of pro-apoptotic PUMA (p53 up-regulated modulator of apoptosis) mRNA using the CD117/LNP system.

Main Results:

• Near-complete correction of hematopoietic sickle cells was achieved using the CD117/LNP editing system.
• In vivo delivery of PUMA mRNA via CD117/LNP modulated HSC function.
• The CD117/LNP system facilitated nongenotoxic conditioning for HSCT.

Conclusions:

• Targeting HSCs in vivo with CD117/LNP-mRNA provides a promising nongenotoxic conditioning strategy for HSCT.
• This platform has the potential for in vivo genome editing to cure genetic disorders, potentially eliminating the need for traditional HSCT.
• The CD117/LNP system represents a significant advancement in gene therapy for blood diseases.