Caution: RNAi

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D. Grimm et al., "Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways," Nature, 441:537-41, 2006. (Cited in 147 papers)

While studying the potential of RNA interference (RNAi) to treat hepatitis in knockout mice, Stanford geneticist Mark Kay and collaborators showed that long-term expression of high levels of short hairpin RNA (shRNA) could kill the animals. Kay says that an overexpression of shRNAs downregulated liver microRNAs, led to cell death, and caused liver failure.

Kay's findings offered what City of Hope researcher, John Rossi, calls "a big yellow caution sign" to researchers studying RNAi-based therapies for potential use in humans. UCLA researcher Irvin Chen found similar results using RNAi to downregulate the CCR5 gene in primary human T cells in vitro. "These shRNAs were toxic to [T] cells over a period of time," says Chen, who is the director of UCLA's AIDS Institute.

Kay says that toxicity could be avoided by altering the RNAi treatment - his lab, for example, used a promoter that dialed down shRNA expression - while still effectively knocking down target genes. "We could get really good sustained knockdown if we just made modifications," Kay says.

Though this paper gave RNAi researchers pause, the approach has not been discarded. "I truly believe that this type of approach is going to be therapeutically useful for a lot of different things," says Kay, who continues to study RNAi treatments for hepatitis. "I think things should move forward in an expeditious but cautious manner."