Therapeutic Area Hematological cancers/disorders (transplantation)
Indication

Hematologic malignancies, bone marrow failure conditions

Objective

To identify novel agonists to be used alone or in combination for expansion of human HSCs

Type of Target Hematopoietic stem cells
IP Status Pending patent applications
Principal Investigator Guy Sauvageau

Competitive Advantages

- Optimized ex vivo expansion of HSCs through the use of a proprietary small molecule i.e. easier production than biological compounds
- Co-development of large-scale bioreactor format for the optimized expansion of HSCs to clinically relevant concentrations
- Optimized lead compound generation through SAR and positive pre-clinical development
- Access to the unique expertise of the Principal Investigator; considered a leader in hematopoietic stem cell characterization

SCIENTIFIC BACKGROUND AND RATIONALE

Hematopoietic stem cell transplantation (HSCT) constitutes one of the most effective strategies for treating patients with hematologic malignancies, bone marrow failure conditions, and a variety of congenital diseases of global concern (e.g. sickle cell anemia and thalassemia). Umbilical cord blood (CB)-derived HSCs represent an appealing source of cells due to large numbers of banked units, which increase the likelihood of finding an HLA-matched donor. However, a low relative abundance of HSCs in CB units has limited their widespread adoption by clinicians. Therefore, the opportunity to use this source of HSCs for life-saving or life-improving treatments would benefit greatly by the ability to robustly amplify these cells ex vivo.

Previous work with various cytokines has not demonstrated clinically useful expansion of HSCs compared to untreated cells. More recently, efforts have shifted focus toward the identification of pharmacological agents that can drive HSC expansion through the use of unbiased high-throughput small molecule screening methodologies. The identification of the purine derivative, StemRegenin1 (SR1), provided a first proof of principle that low molecular weight compounds can have potential utility to promote HSC expansion. Therefore, through the coordinated utilization of in-house high-content screening facilities, extensive medicinal chemistry expertise, and access to a diverse library of proprietary compounds, the multi-disciplinary research team is poised to identify novel hits and develop them to lead compounds that robustly expand CB-derived HSCs ex vivo.

COMPLETED WORK

  • Identification of a lead compound, completely proprietary to IRIC, that robustly expands CB-derived HSCs upon 12-day culture under optimal conditions (Science 2014)
  • Demonstration of ability of the lead compound to maintain long-term HSC phenotype ex vivo and retention of multi-lineage repopulation ability following transplantation
  • Development of optimized formulation through completed structure-activity relationship (SAR)
  • Completed preclinical PK, ADME, and toxicology studies with positive results
  • Co-development of scalable batch-fed bioreactor culture system for large-scale expansion and manipulation of CB-derived HSCs
  • Identification of additional hit compounds that can further expand CB-derived HSCs as well as hits that can differentiate CB-derived short-term progenitors resulting in potentially improved platelet engraftment

UPCOMING MILESTONE

  1. Start of clinical trial

Guy Sauvageau, M.D., F.R.C.P. (C)

  • Head of the Molecular Genetics of Stem Cells Laboratory, IRIC
  • Full Professor, Dept of Medicine, Faculty of Medicine, UdeM
  • Hematologist, Stem Cell Transplant Centre, Maisonneuve-Rosemont Hospital (HMR)
  • Scientific Director, Quebec Leukemia Cell Bank
  • Adjunct Professor, Department of Experimental Medicine, McGill University

Dr. Sauvageau is the Founding Scientific Director and CEO of IRIC. Since 2004, he holds the Canada Research Chair in the Molecular Genetics of Stem Cells. Dr. Sauvageau is an internationally-recognized researcher and clinician, with a research focus on the nature of hematopoietic stem cells (HSCs) and the molecular signals that regulate their proliferation, survival and differentiation. Dr. Sauvageau is the current Chair of the ASH (American Society of Hematology) Scientific Committee on Stem cells. He recently received the Till and McCulloch Award, granted by the Stem Cell Network for recognition of the year’s most influential peer-reviewed article by a Canadian stem cell researcher. Dr. Sauvageau and his team were the first to successfully multiply large quantities of HSCs in vitro. Published in the prestigious scientific journal Cell, this breakthrough is instrumental in accelerating the development of novel treatments for patients waiting for a bone marrow transplant. Over the last fifteen years, Dr. Sauvageau’s work has led to ground- breaking discoveries in understanding the production of hematopoietic stem cells. He and his research team identified the key role of the HOXB4 and Bmi1 genes in regulating HSC self-renewal. His laboratory uses approaches in functional screening to identify genetic networks implicated in this process. Dr. Sauvageau’s team has also developed the use of recombinant proteins allowing for the expansion of the HSCs in clinical settings. His success with the expansion of stem cells paved the way for a major project conducted jointly by the IRIC and MRH to establish the Center of Excellence in Cell Therapy. The team of Dr. Guy Sauvageau at the Université de Montréal’s Institute for Research in Immunology and Cancer (IRIC) made an unprecedented breakthrough thanks to the discovery of a new molecule that expands stem cells from umbilical cord blood. For these reasons, the public has voted this scientific breakthrough “2014 Québec Science Discovery of the Year.”