Angiotensin II and JAK2 put on the pressure


greatly contributed to the conclusion that the characteristics of standard MLV vectors—including preferential integration near transcription start sites and the presence of strong viral enhancers able to activate nearby protooncogenes— preclude further clinical development. A new generation of clinical trials has moved forward, supported by strong preclinical data suggesting that HIV-derived lentiviral vectors or MLV vectors with deletion of strong enhancer elements will be much safer for transduction of HPSCs10–12. Both alternative vector types drive transgene expression from internal promoters that are much less likely to activate protooncogenes near insertion sites, and they have the strong viral enhancers in their LTRs deleted. A trial using HIV vectors to correct HSCs in the devastating neurologic disorder adrenoleukodystrophy has recently been reported, with encouraging signs of clinical disease stabilization. Equally important, this study provides evidence for stable highly polyclonal insertion profiles without the emergence of dominant MDS1–EVI1 clones. Time will tell, but, despite the sobering findings of Stein et al.4, gene therapy is still rolling down the track13.


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