Preclinical Development of a Hematopoietic Stem and Progenitor Cell Bioengineered Factor VIII Lentiviral Vector Gene Therapy for Hemophilia A

Human Gene Therapy
Christopher B DoeringH Trent Spencer

Abstract

Genetically modified, autologous hematopoietic stem and progenitor cells (HSPCs) represent a new class of genetic medicine. Following this therapeutic paradigm, we are developing a product candidate, designated CD68-ET3-LV CD34+, for the treatment of the severe bleeding disorder, hemophilia A. The product consists of autologous CD34+ cells transduced with a human immunodeficiency virus 1-based, monocyte lineage-restricted, self-inactivating lentiviral vector (LV), termed CD68-ET3-LV, encoding a bioengineered coagulation factor VIII (fVIII) transgene, termed ET3, designed for enhanced expression. This vector was shown capable of high-titer manufacture under clinical scale and Good Manufacturing Practice. Biochemical and immunogenicity testing of recombinant ET3, as well as safety and efficacy testing of CD68-ET3-LV HSPCs, were utilized to demonstrate overall safety and efficacy in murine models. In the first model, administration of CD68-ET3-LV-transduced stem-cell antigen-1+ cells to hemophilia A mice resulted in sustained plasma fVIII production and hemostatic correction without signs of toxicity. Patient-derived, autologous mobilized peripheral blood (mPB) CD34+ cells are the clinical target cells for ex vivo transduction usi...Continue Reading

References

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Citations

Aug 28, 2019·Journal of Thrombosis and Haemostasis : JTH·Ian W SmithPaul Clint Spiegel
Nov 30, 2018·Current Protocols in Mouse Biology·Yong Hong ChenBeverly L Davidson
Jul 9, 2020·Haemophilia : the Official Journal of the World Federation of Hemophilia·Ulrike M ReissTsukasa Ohmori
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May 1, 2020·Frontiers in Immunology·Seema R PatelChristopher B Doering
Aug 10, 2020·Current Gene Therapy·Miaojin ZhouDesheng Liang
Oct 17, 2020·American Journal of Hematology·Stacy E CroteauAllison P Wheeler
Feb 10, 2021·Blood Advances·Philip M ZakasDavid Lillicrap
Mar 19, 2021·Frontiers in Bioengineering and Biotechnology·Brady TrevisanGraça Almeida-Porada
Feb 19, 2019·Molecular Therapy. Methods & Clinical Development·Simone Merlin, Antonia Follenzi
Jun 19, 2021·Molecular Therapy. Methods & Clinical Development·Athena L RussellChristopher B Doering
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Methods Mentioned

BETA
enzyme-linked immunosorbent assay
flow cytometry
electrophoresis
ELISA
peptide display
congenic
genetic modification
PCR
mechanical shearing
transgenic

Software Mentioned

Covaris
[UNK] In Silico
SigmaPlot

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