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The humble zebrafish and new drug development
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Use of the zebrafish for drug testing has received a boost as the first drug developed using zebrafish in the initial testing stages has now passed Phase 1 trials of safety and has now entered Phase 2 trials of efficacy. The drug in question is named ProHema and is being developed by Fate Therapeutics after its initial discovery in the laboratory of Dr. Leonard Zon in Boston Children’s Hospital. ProHema is chemically derived from the prostaglandin PGE2, specifically 16,16 dimethyl prostaglandin E2 (dmPGE2). It is being developed as a drug to help improve hematopoietic stem cells (HSCs) count from umbilical cord blood (UCB) in order to improve outcomes of UCB-derived stem cell engraftment. A recent paper in Blood from Dr Zon’s research group outlined the result of the Phase 1 trials (Cutler et al. 2013).

Dr Zon’s research group has been examining the potential of PGE2 in HSC transplant since first publishing a Nature paper in 2007, in which zebrafish were used as a model to screen a panel of biologically active compounds for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. The study revealed that chemicals that enhanced PGE2 synthesis stimulated HSC numbers, while inhibitors of PGE2 synthesis decreased stem cell numbers. A stable derivative of PGE2 was examined and a conserved role for PGE2 in regulation of vertebrate HSC homeostasis was confirmed, opening up the possibility of development for therapeutic stimulation of HSC numbers. Subsequent work by the group showed that PGE2 acts through EP4 in the process of zebrafish lymphoid precursor development while interaction of PGE2 with the Wnt signaling pathways controls HSC engraftment. The recent Blood paper examined the safety of carrying out ex vivo modulation of UCB with dmPGE2 followed by reduced intensity, double UCB transplantation. The results of this Phase 1 trial indicated clear safety along with durable, multilineage engraftment of dmPGE2-treated UCB units. Efficacy trends were also encouraging, as 10 out of 12 treated subjects experienced preferential, long-term engraftment of the dmPGE2 treated UCB.

The process of this work from the initial concept paper in 2007 to successful phase 1 trial data in 2013 indicates the efficacy of the zebrafish as a drug development model which will hopefully be successfully utilised in the future for other drugs.

Sources

CUTLER, C. et al., 2013. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood, 2013

DURAND, E.M. and ZON, L.I., 2010. Newly emerging roles for prostaglandin E2 regulation of hematopoiesis and hematopoietic stem cell engraftment. Current opinion in hematology, 17(4), pp. 308-312

GOESSLING, W. et al., 2009. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell, 136(6), pp. 1136-1147

NORTH, T.E. et al., 2010. PGE2-regulated wnt signaling and N-acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury. Proceedings of the National Academy of Sciences of the United States of America, 107(40), pp. 17315-17320

NORTH, T.E. et al., 2007. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature, 447(7147), pp. 1007-1011
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