The Rett and statins paper explained

Note: This post may be easier to understand if you read this one first.

In the summer, RSRT published an announcement entitled “Statins Suppress Rett Symptoms in Mice“. You know me, always here to help break these things down in plain English. I know that title looks pretty bold and exciting. And it is! But possibly not for the reasons you think.

[The Study]

The study was carried out in Monica Justice’s lab. It was funded by NIHRSRTIRSF, and the Autism Science Foundation.

[The Mice]

In this study, male mice with Mecp2 mutations were inundated with the carcinogen ENU to force mutations in other genes. The mice were then observed to see which ones were doing better with their Rett symptoms. Five particular mice appeared better than the others. In this paper they describe one of these mice; the one that had a mutation in a gene within the cholesterol metabolism pathway. When that gene (called ‘Sqle‘) was mutated, the Rett mice did better.


From this study, it would seem that modifying cholesterol pathways by mimicking the outcome of a Sqle mutation may be a positive thing for girls with Rett. One cannot simply mutate SQLE in humans. So this is where statins come in.   Statins are a group of drugs that modify cholesterol pathways. This is definitely not a case of going and telling your Dr. your daughter should have statins. Now, statins need to be studied even further in mice with Mecp2 mutations. What statin? What dosage? What are the long term effects?  THEN, clinical trials should be undertaken in order to answer those questions in humans.

[Backing up…]

But first, let’s back up and discuss why experiements like this are being done and address a couple questions you may have.

Firsly, why are these experiments usually done on male mice? Good question! Although we know that Rett syndrome happens almost exclusively to females, we know of a few cases where a male is diagnosed. However, it’s a far worse ordeal for the male genome than the female, so males don’t usually live long. Because of the exponentially increased severity of Rett in males, it’s faster and easier to do these experiments on male mice because the success or failure is faster to determine.

To quote Steve Kaminsky of IRSF, “The phenotype is much easier to follow in male mice. They die much sooner, so if you can extend their life, BOOM you have a result. It would take a lot more work to observe changes in females. We scientists are always looking for the cleanest test tube and male mice are that for us.”

A second question you may be asking is why are we looking at other genes when we already know the gene that causes Rett? There are three ways we can seek to address Rett syndrome:

  1. Fix the mutated gene MECP2
  2. Identify the partner genes
  3. Hit the downstream targets or pathways of the MeCP2 protein.

These sorts of studies address that second point. This study sought to address the possibility that, although we can’t yet reverse Rett, perhaps we can find other genes with a relationship with MECP2 that can aid in the recovery of symptoms. The challenge is understanding what pathways we can work with to get around MECP2 mutations. In this study, it would appear that modifying cholesterol pathways may help circumvent the MECP2 problem.

What this paper shows is that cholesterol metabolism has a partnership with MECP2 in some way shape or form. That partnership isn’t known at this point. There are certain parts of the pathways that crossover or are partners with the MECP2 pathways. By using statins, you can change some of the patterns of cholesterol pathways, perhaps them enhancing the MECP2 pathways. Essentially building a serogate carrier to help MECP2 do what it does.

Steve Kaminsky explains it this way, “You may not need a 100% gene reversal or modification to treat Rett syndrome. If we can make incremental increases in the synapses found in Rett with different methods, different cocktails of drugs, each different treatment may result in a percentage of recovery. Like this: what if we only needed to recover the MECP2 gene 60% in order for a girl or woman with Rett to function with speech, hand use…all the things that are difficult at present. What if one compund (like a statin) could recover 10%, 15%  or 20%? And another drug the same? Each different treatment may result in a percentage of recovery and work together to treat the symptoms of Rett syndrome.”

However, there’s a caution here.  We all know Rett syndrome manifests with a range of severity of different symptoms.  Therefore, not all forms of Rett will be helped by a treatment such as this.  At this time, we cannot predict who will benefit from Statins.

[How to take it]

So how do we take this announcement that statins may arrest/treat/cure some of the symptoms of Rett syndrome? We believe that this paper tells us that:

  • There’s a relationship between the cholesterol pathway and MECP2
  • The study also reveals that there are four other genes that have these similar partner relationships (this announcement is focused on the Sqle gene, the one related to cholesterol).

Genetic mutations aren’t good things to have (as we all know so well). But in this case, it seems that the Sqle gene being mutated in a mouse with a mutation on Mecp2, that’s a good thing. What would happen to someone with only a mutation in Sqle and nowhere else is another story. Janice Ascano, PhD, manager of grants and research for IRSF, put it in perspective really well when she told us, “Basically, it’s a case of two wrongs make a right.”

We’re not going to go try to mutate SQLE in people with Rett. But there are compounds out there (statins) that downregulate those other pathways. Downregulating Sqle may create a more even playing field for the two genes. And we’re definitely not going to go and start administering statins to girls with Rett. Steve Kaminsky said it oh-so-well when he told us, “People think ok where do I sign up? You don’t suddenly start administering a statin as a result of a mouse study. Initial discovery now needs to be translated into preclinical data that makes sense to the FDA. Simply making this observation doesn’t mean that we can immediately go and deliver it to a Rett patient in a safe way. This is a great discovery that has a tail of translational research tacked onto it. Now to use that discovery data to complile preclinical data to take to the FDA. That process can take some time. What’s good about this story is that there are a lot of statins so we can move backwards and start looking at drugs already approved and start the translational research of testing it in a mouse. People take statins every day to help control their metabolism.”

[What now?]

Well, as said previously, this just means that there’s an open door to exploring the possibilities that statins may have other medicinal values than simply modifying cholesterol metabolism. We’ve discovered that this other gene affects something. Now to do all the homework that goes with that. An exciting thing to take away from this is the idea that other scientists who work with cholesterol could now jump into the Rett scene. They just need access to the mice.

This post was made possible by contributions from:

  • Steve Kaminsky, Ph.D. – Chief Science Officer, IRSF
  • Janice Ascano, Ph.D. – Manager of Grants and Research, IRSF
  • Kori Coates, Executive Director, Cure Rett
  • Paige Nues, Director of Family Support, IRSF