Development of an automated Umbilical Cord Blood Hematopoietic Stem Cell expansion by endothelial cells for transplantation

DESCRIPTION provided by applicant Initially umbilical cord blood UCB transplantation was limited to children given the low cell dose infused Both related and unrelated cord blood transplants have been performed with high rates of success for a variety of hematologic disorders and metabolic diseases in the pediatric setting In more recent years the use of UCB transplants has expanded and results for adult umbilical cord blood transplantation have improved but not without a number of challenges As little as of the world wide inventory of UCB may be of insufficient total nucleated cell count TNC for both adult and pediatric transplants The minimal TNC count results in a profound delay in recovery of the patients leaving them susceptible to numerous lethal complications In order to realize the full potential and impact UCB can have for patients treated for hematological malignancies ex vivo expansion of the UCB material is necessitated Current mechanisms for the expansion of Hematopoietic Stem and Progenitor Cells HSPCs lack the proper microenvironment possibly explaining the clinical trial failures Evidence continues to mount from numerous groups detailing the indispensable role endothelial cells ECs have in promoting the HSPC via the secretion of numerous growth factors termed angiocrine factors Traditional mechanisms of culturing endothelial cells have not been permissible to recapitulate the in vivo microenvironment generated by ECs This limitation has been eliminated in ECs by the VeraVec EC platform by the addition of the Ad E ORF protein VeraVec ECs have repeatedly demonstrated their capacity to expand HSPCs with high fidelity and high engraftability in co culture conditions Pre clinical data demonstrates the capacity for the platform to expand UCB fold over days Importantly this expanded material maintains all aspect of the HSPC phenotype including long term engraftment serial transplant and multilineage commitment equal to unmanipulated UCB However large scale co cultures of HSPCs and VeraVec ECs are labor intensive logistically challenging and consume large quantities of reagents in cGMP compliant facilities These barriers make the adoption of the VeraVec EC platform for HSPC unlikely We therefore propose to introduce the co culture into the TerumoBCT Quantum hollow fiber bioreactor to automate the expansion The end product will be an automated large scale high fidelity expansion without sacrificing any benefits of the VeraVec platform PUBLIC HEALTH RELEVANCE The proposal seeks to develop an automated expansion platform for umbilical cord blood UCB towards hematopoietic stem cell transplantation As to date the advantages of UCB transplantation were realized only in children due to the limited amount in transplantable material The successful completion of the proposed project holds the promise of significantly reducing blood cancer mortality rates