Bone marrow-targeted extracellular vesicles as a novel non-viral gene editor delivery platform

Despite advances in gene therapy techniques, novel methods that facilitate tight targeting of gene therapy products to specific tissues and cell types are necessary to achieve widespread clinical applicability. Inherited hematologic diseases represent an ideal target for novel genetic therapies, as gene therapy approaches can bypass the significant limitations associated with bone marrow transplantation and symptomatic treatment. Extracellular vesicles (EVs) capable of targeting hematopoietic stem cells (HSCs) are a promising option for the targeted delivery of gene editor machinery to treat genetic hematologic diseases. Successful system development represents a billion-dollar market opportunity that will be defined by the ability to show: (1) targeting specificity, (2) a favorable safety profile, and (3) efficient in vivo delivery of gene editor machinery. We have developed a proprietary EV-based system for in vivo nucleic acid and protein delivery that specifically targets HSCs in bone marrow, is amenable to large scale/commercial manufacture, and presents with low immunogenicity which confers unique potential for repeat dosing. Our hypothesis is that the STRM.BIO EV-based system can be efficiently loaded with gene editor cargo, safely home to the bone marrow following intravenous delivery, and effectively edit targeted genes in HSCs. With funds provided by this Phase II award, we will (1) establish SOPs for loading STRM.BIO EVs with cargo, (2) characterize the biodistribution and delivery pattern of cargo-loaded EVs, and (3) verify feasibility of STRM.BIO EVs for in vivo cargo delivery in a mouse model of human genetic hematologic disease. The current proposal aims to establish pre-clinical proof-of-concept support for the use of our proprietary system as a non-viral, in vivo genome editor delivery system for the treatment of inherited hematologic diseases.