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Auto-expansion of in vivo HDAd-transduced hematopoietic stem cells by constitutive expression of tHMGA2

Molecular Therapy - Methods & Clinical Development, ISSN: 2329-0501, Vol: 32, Issue: 3, Page: 101319
2024
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  • Captures
    4
  • Mentions
    1
    • News Mentions
      1
      • News
        1

Most Recent News

Study Results from University of Washington Update Understanding of Gene Therapy (Auto-expansion Of In Vivo hdad-transduced Hematopoietic Stem Cells By Constitutive Expression of Thmga2)

2024 OCT 14 (NewsRx) -- By a News Reporter-Staff News Editor at Gene Therapy Daily News -- Investigators discuss new findings in Biotechnology - Gene

Article Description

We developed an in vivo hematopoietic stem cell (HSC) gene therapy approach that does not require cell transplantation. To achieve therapeutically relevant numbers of corrected cells, we constructed HSC-tropic HDAd5/35++ vectors expressing a 3′ UTR truncated HMGA2 gene and a GFP reporter gene. A SB100x transposase vector mediated random integration of the tHMGA2/GFP transgene cassette. HSCs in mice were mobilized by subcutaneous injections of G-CSF and AMD3100/Plerixafor and intravenously injected with the integrating tHMGA2/GFP vector. This resulted in a slow but progressive, competitive expansion of GFP + PBMCs, reaching about 50% by week 44 with further expansion in secondary recipients. Expansion occurred at the level of HSCs as well as at the levels of myeloid, lymphoid, and erythroid progenitors within the bone marrow and spleen. Importantly, based on genome-wide integration site analyses, expansion was polyclonal, without any signs of clonal dominance. Whole-exome sequencing did not show significant differences in the genomic instability indices between tHGMGA2/GFP mice and untreated control mice. Auto-expansion by tHMGA2 was validated in humanized mice. This is the first demonstration that simple injections of mobilization drugs and HDAd vectors can trigger auto-expansion of in vivo transduced HSCs resulting in transgene-marking rates that, theoretically, are curative for hemoglobinopathies.

Bibliographic Details

Wang, Hongjie; Georgakopoulou, Aphrodite; Nizamis, Evangelos; Mok, Ka Wai; Eluère, Raïssa; Policastro, Robert A; Valdmanis, Paul N; Lieber, André

Elsevier BV

Biochemistry, Genetics and Molecular Biology

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