Choose your Statin with Care in FXS, NF1 and idiopathic Autism

There are several old posts in this blog about the potential to treat some autism using statins; this has nothing to do with their ability to lower cholesterol. 

Statins are broadly anti-inflammatory but certain statins do some other particularly clever things. This led me to use Atorvastatin and Fragile-X researchers to use Lovastatin.

Fragile X is suggested by an elongated face and big/protruding ears; 

other features include MR/ID and autism.

I was recently forwarded a Scottish study showing why Simvastatin does not work in Fragile X syndrome, but Lovastatin does.

Fragile X mental retardation protein (FMR1) acts to regulate translation of specific mRNAs through its binding of eIF4E (see chart below). In people with Fragile X, they lack the FMR1 protein. Boys are worse affected than girls, because females have a second X chromosome and so a "spare" copy of the gene.

         Simvastatin does not reduce ERK1/2 or mTORC1 activation in the Fmr1-/y hippocampus.

So  ? = Does NOT inhibit

The researchers in Scotland did not test Atorvastatin in their Fragile X study.

The key is to reduce Ras. In the above graphic it questions does Simvastatin inhibit RAS and Rheb.

RASopathies have been covered in this blog. Too much of the Ras protein is a common feature of much ID/MR. Investigating RAS took me to PAK1 inhibitors and the experimental drug FRAX486. This drug was actually developed to treat Fragile X; it is now owned by Roche. At least one person is using FRAX486 to treat autism.

You might wonder why the researchers do not just try Lovastatin in humans with Fragile X.  Unfortunately, Lovastatin was never approved as a drug in Scotland, or indeed many other countries.  Some researchers just assumed they could substitute Simvastatin, which on paper looks a very similar drug and one that crosses the blood brain barrier better than Lovastatin.

Lovastatin, not simvastatin, corrects core phenotypes in the fragile X mouse model

The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause of autism and intellectual disability. The therapeutic efficacy of lovastatin is being tested in clinical trials for FX, however the structurally similar drug simvastatin has been proposed as an alternative due to an increased potency and brain penetrance. Here, we perform a side-by-side comparison of the effects of lovastatin and simvastatin treatment on two core phenotypes in the Fmr1-/y mouse model. We find that while lovastatin normalizes excessive hippocampal protein synthesis and reduces audiogenic seizures (AGS) in the Fmr1-/y mouse, simvastatin does not correct either phenotype. These results caution against the assumption that simvastatin is a valid alternative to lovastatin for the treatment of FX.  

Although we propose the beneficial effect of lovastatin stems from the inhibition of ERK1/2-driven protein synthesis, it is important to note that statins are capable of affecting several biochemical pathways. Beyond the canonical impact on cholesterol biosynthesis, statins also decrease isoprenoid intermediates including farnesyl and geranylgeranyl pyrophosphates that regulate membrane association for many proteins including the small GTPases Ras, Rho and Rac [18, 46, 48, 49]. The increase in protein synthesis seen with simvastatin could be linked to altered posttranslational modification of these or other proteins. Indeed, although we see no change in mTORC1-p70S6K signaling, other studies have shown an activation of the PI3 kinase pathway that could be contributing to this effect [32]. However, our comparison of lovastatin and simvastatin shows that there is a clear difference in the correction of pathology in the Fmr1-/y model, suggesting that the impact on ERK1/2 is an important factor in terms of pharmacological treatment for FX.  There are many reasons why statins would be an attractive option for treating neurodevelopmental disorders such as FX. They are widely prescribed worldwide for the treatment of hypercholesterolemia and coronary heart disease [50], and safely used for longterm treatment in children and adults [46]. However, our study suggests that care should be taken when considering which statin should be trialed for the treatment of FX and other disorders of excess Ras. Although the effect of different statins on cholesterol synthesis has been well documented, the differential impact on Ras-ERK1/2 signaling is not well established. We show here that, contrary to lovastatin, simvastatin fails to inhibit the RasERK1/2 pathway in the Fmr1-/y hippocampus, exacerbates the already elevated protein synthesis phenotype, and does not correct the AGS phenotype. These results are significant for considering future clinical trials with lovastatin or simvastatin for FX or other disorders of excess Ras. Indeed, clinical trials using simvastatin for the treatment of NF1 have shown little promise, while trials with lovastatin show an improvement in cognitive deficits [28-30]. We suggest that simvastatin could be similarly ineffective in FX and may not be a suitable substitute for lovastatin in further clinical trials.

Conclusion

If you are treating Fragile X, best to start with Lovastatin and see if it helps.  In theory it might also help NF1 (Neurofibromatosis Type 1).

It looks to me that Atorvastatin also inhibits the relevant pathway and does much more besides that (PTEN, BCL2 etc)

Atorvastatin inhibits insulin synthesis by inhibiting the Ras/Raf/ERK/CREB pathway in INS-1 cells

What is Roche doing with FRAX486?