Opening Marrow Niches in Patients Undergoing Autologous Hematopoietic Stem Cell Gene Therapy

Hematol Oncol Clin North Am. 2017 Oct;31(5):809-822. doi: 10.1016/j.hoc.2017.06.003. Epub 2017 Jul 28.

Abstract

Successful gene therapy for genetic disorders requires marrow niches to be opened to varying degrees to engraft gene-corrected hematopoietic stem cells (HSC). For example, in severe combined immunodeficiency, relatively limited chimerism is necessary for both T- and B-cell immune reconstitution, whereas for inborn errors of metabolism maximal donor chimerism is the goal. Currently, alkylating chemotherapy is used for this purpose. Significant pharmacokinetic variability exists in drug clearance in children less than 12 years old. Thus, pharmacokinetic monitoring is needed to achieve the targeted exposure goal for busulfan.

Keywords: Conditioning; Gene therapy; Hemoglobinopathies; Inborn errors of metabolism; Marrow niches; Pharmacokinetics; Primary immune deficiency.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Bone Marrow / metabolism*
  • Gene Expression
  • Gene Transfer Techniques
  • Genetic Therapy* / methods
  • Hematopoietic Stem Cell Transplantation*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism*
  • Hemoglobinopathies / genetics
  • Hemoglobinopathies / therapy
  • Humans
  • Metabolism, Inborn Errors / genetics
  • Metabolism, Inborn Errors / therapy
  • Severe Combined Immunodeficiency / genetics
  • Severe Combined Immunodeficiency / therapy
  • Stem Cell Niche*
  • Transduction, Genetic
  • Transgenes
  • Transplantation Conditioning
  • Transplantation, Autologous

Substances

  • Antineoplastic Agents