Megakaryocyte- and megakaryocyte precursor–related gene therapies

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.

The biology of the platelet with special reference to inflammation wound healing and immunity

“…Anti-platelet therapy is an increasingly used option in non-hemostatic disorders as for example the use of P2Y 12 inhibitors to reduce inflammation or blockers of β3 integrins in metastasis and tumor growth (86,195). An alternative and very promising approach is to genetically modify progenitor cells or MKs so that platelets are produced with α-granules containing new proteins of therapeutic benefit such as FVIII as a treatment for hemophilia or TRAIL for prostrate cancer (196)(197). This type of approach may ultimately be used for lifelong therapies in major illnesses including cardiovascular disease, other forms of cancer and Alzheimer's disease but also many others.…”

Delivery of mRNA to platelets using lipid nanoparticles

“…However, there are challenges in modifying platelets. Currently, hematopoietic stem cells need to be transfected to increase protein expression in platelets, and the use of such cells in patients requires intensive preclinical procedures or major advances in ex vivo platelet culturing and production 6,7 . An alternative approach would be to directly alter donor-derived platelets ex vivo prior to transfusion.…”

Targeting expression to megakaryocytes and platelets by lineage‐specific lentiviral vectors

“…Retroviral vectors for specific expression in platelets via modification of HSCs are also of interest for gene and cell therapies targeting proteins to platelets. This has been investigated for the correction of platelet disorders [7,8] or the expression of clotting factors in platelets to treat hemophilia A and B [9][10][11][12][13][14].…”