Megakaryocyte- and megakaryocyte precursor-related gene therapies

Blood. 2016 Mar 10;127(10):1260-8. doi: 10.1182/blood-2015-07-607937. Epub 2016 Jan 19.

Abstract

Hematopoietic stem cells (HSCs) can be safely collected from the body, genetically modified, and re-infused into a patient with the goal to express the transgene product for an individual's lifetime. Hematologic defects that can be corrected with an allogeneic bone marrow transplant can theoretically also be treated with gene replacement therapy. Because some genetic disorders affect distinct cell lineages, researchers are utilizing HSC gene transfer techniques using lineage-specific endogenous gene promoters to confine transgene expression to individual cell types (eg, ITGA2B for inherited platelet defects). HSCs appear to be an ideal target for platelet gene therapy because they can differentiate into megakaryocytes which are capable of forming several thousand anucleate platelets that circulate within blood vessels to establish hemostasis by repairing vascular injury. Platelets play an essential role in other biological processes (immune response, angiogenesis) as well as diseased states (atherosclerosis, cancer, thrombosis). Thus, recent advances in genetic manipulation of megakaryocytes could lead to new and improved therapies for treating a variety of disorders. In summary, genetic manipulation of megakaryocytes has progressed to the point where clinically relevant strategies are being developed for human trials for genetic disorders affecting platelets. Nevertheless, challenges still need to be overcome to perfect this field; therefore, strategies to increase the safety and benefit of megakaryocyte gene therapy will be discussed.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Genetic Therapy / methods*
  • Hematologic Diseases / genetics
  • Hematologic Diseases / metabolism
  • Hematologic Diseases / pathology
  • Hematologic Diseases / therapy*
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Integrin alpha2 / biosynthesis
  • Integrin alpha2 / genetics
  • Megakaryocyte Progenitor Cells / metabolism*
  • Megakaryocyte Progenitor Cells / pathology
  • Megakaryocytes / metabolism*
  • Megakaryocytes / pathology
  • Transgenes

Substances

  • ITGA2B protein, human
  • Integrin alpha2