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November 26, 2008

Statin Therapy and Cognitive Deficits Associated With Neurofibromatosis Type 1—Reply

JAMA. 2008;300(20):2369-2370. doi:10.1001/jama.2008.688

In Reply: Dr Jansen raises questions about the rationale of our trial and the value of the NF1 mouse model for translational research.1 It is important to re-emphasize that the NF1 protein is not involved in cholesterol metabolism. NF1 is a negative regulator of RAS activity, and increased RAS signaling has been shown to underlie the learning deficits of Nf1+/– mice.2 The rationale to treat the cognitive deficits with statins was based on 2 fundamental findings in the cancer literature: RAS requires posttranslational isoprenylation for proper signaling, and RAS transforming activity can be suppressed by reducing the synthesis of the isoprenyl groups by statins.1,3,4 The molecular and behavioral deficits of Nf1+/– mice can indeed be ameliorated by decreasing RAS activity, either genetically or by administrating farnesyl transferase inhibitors or statins.1,2

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