Session: Hot Topic: Learnings From Managing Immunogenicity Risks to Protein Based Therapeutics; Need to Pivot for Cell and Gene Therapies or 1 Size Fits All?
Enhancing Engraftment of Hematopoietic Stem Cells Using CD117-Saporin Immunotoxin: Advantages in Gene Therapy, Allotransplantation and Tolerance Induction
Chief, Laboratory of Molecular Immunology NIAID, NIH
Gene therapy for gain-of-function genetic disorders requires correction or silencing of the mutant allele(s) in hematopoietic stem cells (HSCs) ex vivo followed by efficient engraftment of the cells following transplantation in the bone marrow. This presentation will describe preclinical development of an efficient protocol for cure of the autosomal dominant gain-of-function disease WHIM syndrome immunodeficiency that couples CRISPR/Cas9-mediated mutant allele silencing in HSCs with efficient and selective engraftment of edited HSCs using CD117-saporin immunotoxin conditioning. The disease gene in WHIM syndrome encodes the chemokine receptor CXCR4 which is critical for homeostatic leukocyte trafficking and positioning, including homing, positioning and retention of HSCs in the bone marrow. The silencing of the mutated CXCR4 allele confers a selective advantage for engraftment of transplanted HSCs without overt safety costs, and the non-genotoxic conditioning by CD117-saporin eliminates upfront toxicity associated with genotoxic conditioning agents, without sacrificing engraftment efficiency.
Learning Objectives:
Upon completion, participants will be able to understand the genetic, biochemical and cellular basis of WHIM syndrome immunodeficiency.
Upon completion, participants will be able to understand the mechanism of action of CRISPR/Cas9 gene editing.
Upon completion, participants will be able to understand the value of non-genotoxic conditioning for bone marrow transplantation.
