Total Body Irradiation Must Be Delivered at High Dose for Efficient Engraftment and Tolerance in a Rhesus Stem Cell Gene Therapy Model

Overview

Journal Mol Ther Methods Clin Dev

Publisher Cell Press

Date 2016 Sep 22

PMID 27652288

Citations 8

Authors

Naoya Uchida

R Patrick Weitzel

Anna Shvygin

Luke P Skala

Lydia Raines

Aylin C Bonifacino

Allen E Krouse

Mark E Metzger

Robert E Donahue

John F Tisdale

Affiliations

Soon will be listed here.

Abstract

Reduced intensity conditioning (RIC) is desirable for hematopoietic stem cell (HSC) gene therapy applications. However, low gene marking was previously observed in gene therapy trials, suggesting that RIC might be insufficient for (i) opening niches for efficient engraftment and/or (ii) inducing immunological tolerance for transgene-encoded proteins. Therefore, we evaluated both engraftment and tolerance for gene-modified cells using our rhesus HSC gene therapy model following RIC. We investigated a dose de-escalation of total body irradiation (TBI) from our standard dose of 10Gy (10, 8, 6, and 4Gy), in which rhesus CD34(+) cells were transduced with a VSVG-pseudotyped chimeric HIV-1 vector encoding enhanced green fluorescent protein (GFP) (or enhanced yellow fluorescent protein (YFP)). At ~6 months after transplantation, higher-dose TBI resulted in higher gene marking with logarithmic regression in peripheral blood cells. We then evaluated immunological tolerance for gene-modified cells, and found that lower-dose TBI allowed vigorous anti-GFP antibody production with logarithmic regression, while no significant anti-VSVG antibody formation was observed among all TBI groups. These data suggest that higher-dose TBI improves both engraftment and immunological tolerance for gene-modified cells. Additional immunosuppression might be required in RIC to induce tolerance for transgene products. Our findings should be valuable for developing conditioning regimens for HSC gene therapy applications.

Citing Articles

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