By Thomas Insel on December 4, 2014
Marfan syndrome is a rare genetic disease of connective tissue caused by a mutation in FBN1, the gene that encodes the protein fibrillin-1. People with Marfan syndrome tend to be unusually tall with long fingers and toes and often have curvature of the spine. But the most serious problems involve the heart and especially the aorta. Weakening of the connective tissue in the aorta leads to dilation or sometimes aneurysms, which can be fatal if they rupture. Mice with a Marfan mutation of FBN1 show changes in fibrillin-1 and develop the same changes in the aorta found in humans with the syndrome.
In fact, Marfan syndrome has been my favorite example of the cycle of translational research: find the genetic mutation in patients, induce the mutation in mice, identify the effects of the mutation in mice, find a treatment for the mice, then move that treatment back into patients. This translational cycle showed all the signs of success in Marfan syndrome. Not only did the mice develop a key aspect of the human syndrome, but losartan, a drug already available on the market, blocked the effects of misfolded fibrillin-1 and consistently prevented the aortic disease in mice. When initial studies of losartan in patients with Marfan syndrome looked promising, there was every reason to believe that the translational cycle would deliver the first treatment to target the fundamental defect in this genetic disease. So the report last month in the New England Journal of Medicine that losartan was not more effective than the usual treatment with a beta-blocker was deeply disappointing.1 Although the usefulness of losartan is not foreclosed, neither is it a magic bullet.2 Disappointing but perhaps not entirely surprising. The final step in this translational cycle appears to be the hardest. That has been especially true for brain disorders. Over the past decade we have cured nearly every brain disorder, from autism to Alzheimers, in mice, but these effects rarely translate to patients. In fact, the cynical joke among clinical researchers is that if you are going to develop a brain disorder, first become a mouse.
Why have mouse cures not become human cures? In many cases, such as in Rett syndrome , the mouse cure requires a genetic manipulation that is not yet possible for human patients. In some cases, as with Marfan syndrome, a drug is already available, but the drug effect observed in mice does not translate to humans. For some disorders, like schizophrenia, mice may not have the relevant brain areas to represent the effect needed in humans. There are a variety of reasons, but the result is now becoming more the rule than the exception: treatment effects in mice do not predict treatment effects in humans.