The MArrowMiner for Gene & CELL DELIVERY
In an ongoing study funded by the BMGF, we seek to determine whether the MarrowMiner (MM) device can be used to effectively infuse gene vectors into the intraosseous bone marrow space to enable in-vivo gene therapy for a variety of genetic and infectious diseases. ‘ Secondary aims include: to refine gene delivery methods as well as to develop and build an optimized ‘MarrowRx’ device specifically for intra osseous (IO) gene delivery. ( In collaboration with Dr. Hans-Peter Kiem and colleagues at the Fred Hutchinson Cancer Center/University of Washington), and others. ) Need: A growing number of genetic (i.e., sickle cell disease and thalassemia) and infectious diseases (i.e., HIV) have the potential to be treated or cured by new forms of gene therapy. Autoloagous stem cell harvest and ex vivo gene transduction and clinical delivery of genetically modified cell delivery is capital and resource intensive. The ability to administer genetic vectors in an intraosseous (IO) manner for direct in vivo hematopoietic stem cell transduction may enable efficient and cost-effective therapies and cures. Standard bone marrow needles can only access a limited region of the marrow cavity. A means to effectively deliver IO gene therapy in a minimally invasive manner directly to the marrow cavity could enable the field of gene therapy and facilitate pre-clinical and clinical research while setting the stage for impactful cures at a global scale.
Background & Rationale: The MarrowMiner is a novel, FDA-cleared medical device for the harvest of bone marrow that is designed to access the bone marrow cavity in a rapid, minimally invasive manner under local anesthesia via single entry point (e.g., iliac crest or long bone) to harvest rich bone marrow for use bone marrow transplantation and a wide array of regenerative medicine approaches using marrow-derived cells. The sterile, disposable MM device consists of an ergonomic, powered handle attached to a rotating FlexShaft which enters the marrow cavity via trocar at a single-entry point. The FlexShaft has a blunt tip containing 3 holes for aspiration or delivery of liquids that enables movement through cancellous bone marrow cavity without puncturing the outer cortical bone. The rotating FlexShaft follows the contours and shape of the marrow cavity as it moves. This enables the harvest of marrow-derived cells over a wide area of the marrow cavity (with marrow less diluted by peripheral blood than serial bone punctures and small volume aspirates performed by standard aspirate needles). By utilizing the MM to access the marrow cavity to deliver therapy, instead of harvesting marrow, genetic vectors could be delivered IO across a significant area of marrow space; if so, the MM may facilitate efficient in vivo gene therapy for a number of potential therapeutic applications. IO delivery will be compared to IV gene vector delivery in NHP.
Summary to date : In two separate experimental sessions at the UW Animal Facility with anesthetized NHP Rhesus) in March 2024 we successfully demonstrated MarrowMiner enabled intraosseous (IO) delivery of simulated gene vector while optimizing the procedure and techniques. The key aims were completed which were to develop a procedure to deliver targeted volume and a dose of gene vector across the length of the intramedullary space of the femur.
We demonstrated: 1. Ability of the MarrowMiner to safely and readily enter and move from proximal femur into the distal femur through the entire femoral length (~10cm) in live NHP. 2. Successful MarrowMiner placement and delivery in 4/4 femurs. 3. Visualized delivery of saline (mixed 3:1 with iodinated radiopaque contrast agent) delivered ~2ml at a controlled rate (1-2ml/minute) while slowly retracting the rotating MM FlexShaft. 4. Visualized by Fluoroscopy the delivery and retention of the saline+ contrast agent within the path of delivery. 5. Visualization of retained contrast agent within marrow cavity for > 20 minutes. 6. The NHP tolerated the procedure well, with no sequelae or observed morbidity post procedure.
The 3 NHP will receive IO AAV beginning in August of 2024, and will be compared to NHP receiving IV administration of identical dose. Read outs will be obtained in the 6 months after IO and IV delivery.
