Ex Vivo Pharmacologic Modulation of Hematopoietic Stem Cells

Hematopoietic stem cell transplantation represents a potentially life-saving treatment option for children and adults afflicted with hematologic malignancies (e.g., leukemia and lymphoma) or certain other non-malignant orphan diseases such as inherited metabolic or lysosomal storage disorders (LSDs), hemoglobinopathies (e.g., sickle cell disease, and beta-thalassemia), aplastic anemia and immune deficiencies. The number of procedures performed and the breadth of diseases treated has increased steadily over the past two decades – approximately 60,000 hematopoietic stem cell (HSC) transplants are performed on a worldwide annual basis in patients with hematologic malignancies alone, and more than 50 rare diseases have now been treated with curative intent through HSC transplantation.

The source of HSCs used for transplantation has also evolved considerably over the past several decades. Most recently, cord blood has emerged as an attractive source of HSCs for patients lacking a suitable donor: ease of collection, prompt availability and immunological naivete´ of immune cells (leading to reduced incidence and severity of graft-versus-host disease and less stringent HLA-matching requirements) are all superior characteristics unique to cord blood. Cord blood currently represents the fastest growing cell source for use in HSC transplantation.

Despite these significant advantages of cord blood as a stem cell source, the full clinical potential of cord blood for use in treating patients with hematologic malignancies and other rare diseases is currently limited by the low numbers of HSCs present in a given cryopreserved cord blood unit. This low stem cell dose leads to higher rates of graft failure, delayed neutrophil recovery and a higher risk of serious infections and early mortality compared to standard donor transplants.

Our lead product candidate, PROHEMA®, is a pharmacologically modulated HSC therapeutic derived from umbilical cord blood. Produced through a proprietary, two-hour, ex vivo cell modulation process that results in rapid and supra-physiologic changes in key cell properties, PROHEMA® has been shown to enhance hematopoietic reconstitution in preclinical models through several unique mechanisms of action, including enhanced homing, or migration, of HSCs to the bone marrow niche as well as increased HSC proliferation and survival.

We have established initial human proof-of-concept for PROHEMA® in the clinical setting by demonstrating accelerated and durable engraftment of HSCs within the bone marrow. We are presently advancing PROHEMA®in Phase 2 clinical development for hematologic malignancies. We are also pursuing the development of pharmacologically optimized HSC therapeutics for the treatment of certain LSDs (e.g. Krabbe disease and Hurler syndrome) where HSCs have demonstrated the ability to reconstitute the blood system as well as home to and engraft within the central nervous system, where they can provide normal enzyme replacement.

Selected publications:

  • Cutler, C., Multani, P., Robbins, D., Kim, H., Le, T., Hoggatt, J., Pelus, L., Desponts, C., Chen, Y., Rezner, B., Armand, P., Koreth, J., Glotzbecker, B., Ho, V., Alyea, E., Isom, M., Kao, G., Armant, M., Silberstein, L., Hu, P., Soiffer, R., Scadden, D., Ritz, J., Goessling, W., North, T., Mendlein, J., Ballen, K., Zon, L., Antin, J., Shoemaker, D. Prostaglandin-Modulated Umbilical Cord Blood Hematopoietic Stem Cell Transplantation. Blood publication link.
  • Hoggatt, J., Singh, P., Sampath, J., and Pelus, L. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood 113, 5444-5455 (2009).
  • Zon, L. Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal. Nature 453, 306-313 (2008).
  • North, T., Goessling, W., Walkley, C., Lengerke, C., Kamden, R., Lord, A., Weber, G., Bowman, T., Jang, I., Grosser, T., FitzGerald, G., Daley, G., Orkin, S., and Zon, L. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 447, 1007-1012 (2007).