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15-PGDH inhibition in multiple models of murine BMT
In overview, treatment with (+)-SW209415 significantly accelerates neutrophil recovery after HSCT even in mice that are also receiving G-CSF, suggesting that this approach can provide an additive benefit over current standard therapy.
(+)-SW209415 is effective in promoting hematopoietic recovery after bone marrow transplantation in aged mice
Our prior studies demonstrating the effects of the 15- PGDH inhibitor SW033291 on accelerating hematopoietic reconstitution were performed with donor and recipient mice of 8-10 weeks of age, and thus roughly approximat- ing humans of late teenage years.22 Humans undergoing HSCT are, however, primarily middle-aged and older, and the potency of human HSC in hematopoietic reconstitu- tion is recognized to decline with age.23-25 To investigate potential age-related dependencies of the effects of 15- PGDH inhibition, both in inducing tissue PGE2 and in pro- moting hematopoietic reconstitution, we also studied mice aged 52 weeks old, an age at which females are approaching reproductive senescence and exhibiting other biological changes of late middle-aged humans. Reassuringly, in these older mice a single dose of (+)- SW209415 induced a 2-fold increase in bone marrow PGE2 at 3 h after injection (Figure 4A), essentially recapit- ulating the same pharmacodynamic effect demonstrated in 8-week old mice (Figure 1D). We next investigated the activity of (+)-SW209415 in accelerating recovery from
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HSCT in these older mice, performing murine HSCT in which both the bone marrow donor and lethally irradiat- ed bone marrow recipient mice were 52 weeks old. Most notably, compared to control older mice, (+)-SW209415- treated older mice had double the number of neutrophils on each of days 8, 12, and 18 after transplantation (P=0.01) (Figure 4B). Moreover, we also observed an ~2-fold upward trend in the total number of SKL cells in the (+)- SW209415-treated cohort (Online Supplementary Figure S7). In overview, these observations confirm that the approach of inhibiting 15-PGDH to accelerate recovery from HSCT remains efficacious even when both transplant donor and recipient animals are older, which may model older per- sons.
(+)-SW209415 accelerates hematopoietic recovery in hematopoietic stem cell transplant recipient mice that receive a “high-dose” inoculum of donor cells
(+)-SW209415 demonstrates activity in accelerating hematopoietic recovery in multiple different models of HSCT. However, hematopoietic recovery following HSCT can also be accelerated by providing a larger inocu- lum of transplanted donor cells. To investigate whether the benefits from inhibiting 15-PGDH are independent of the dose of transplanted donor cells, we re-examined our initial studies of murine HSCT using an escalated dose of 2x106 donor bone marrow cells. As expected, compared to mice transplanted with 500,000 donor cells, mice receiv- ing a larger inoculum of 2x106 donor cells showed greater
Figure 4. (+)-SW209415 is effective in promoting hematopoietic recovery after bone marrow transplantation (BMT) in aged mice. (A) Fifty-two-week old aged C57/Bl6J female mice were administered a single intraperitoneal dose of 2.5 mg/kg (+)-SW209415. Animals were sacrificed at the time points indicated after injection and bone marrow flushed for analysis of PGE2 via enzyme-linked immunosorbent assay (3 mice/arm). (B) Fifty-two-week old female donor and lethally irradiated (11 Gy) recipient C57/BL6J aged mice were used in this study. Mice were transplanted with 500x103 total bone marrow cells and treated with either vehicle or 2.5 mg/kg (+)-SW209415 (twice daily, intraperitoneally). The graphs display the means and Standard Error of Mean of peripheral blood neu- trophil counts on day 8, 12, and 18 after BMT (10 mice/arm). *Student t-test P<0.05.
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