Transient Modified-RNA Expression of Activation Factor Promotes Adult Hematopoietic Stem Cell Expansion

Background & Unmet Need

• Hematopoietic Stem Cell (HSC) transfer and transplantation is a life-saving treatment for many diseases, including cancers and blood disorders
• Human mobilized peripheral blood (mPB) is the most accessible source of Hematopoietic Stem and Progenitor Cells (HSPCs)
• However, there can be insufficient numbers of available transplantable mPB HSPCs following extraction or following ex-vivo genetic therapy
• Moreover, mPB HSPCs are much less proliferative than HSPCs from other sources, such as cord blood, and are less likely to respond to current expansion protocols
• Unmet Need: Activation methods for mPB-derived HSPC robust expansion for successful stem cell transplants resulting with full recovery and reconstitution of blood and immune systems

Technology Overview

• The Technology: A method for ex-vivo activation of HSPC expansion using a modified-RNA to overexpress a defined transcription factor
• The Discovery: The inventors have discovered a master transcriptional regulator for HSPC activation, which can direct HSPC regenerative expansion from a quiescent non-cycling state
• This activation factor mediates the crosstalk between HSPCs and their niche and sensitizes them to expansionary regenerative signals
• Treatment with modified RNA to induce over-expression of this factor or downstream activation factors can prime HSPCs for robust expansion
• PoC Data: Human adult mPB HSPCs treated with this modified-RNA had increased expansion and superior engraftment capacity in vivo matching that of neonatal cord blood-derived HSPCs

Technology Applications

• Ex-vivo, pre-transplantation expansion of adult bone marrow or peripheral blood mobilized HSPCs
• Use for patients with poorly-mobilizing mPBs (e.g. due to genetic factors, diabetes, immunotherapy, chemotherapy)
• Pre-engraftment expansion of HSCs following successful genetic therapy for gene replacement (e.g. beta-thalassemia)

Technology Advantages

• Increased adult HSPC activation and expansion
• Expanded HSCs successfully engraft when transplanted displaying higher numbers of repopulating cells
• Transient expression using modified-RNA technology limits the risk of tumorigenesis or stem cell exhaustion associated with constitutive expression of activation factors