Rett Syndrome Research and the Boston Studies

I've been doing a lot of research over the last month on papers published relating to Rett Syndrome. There's been plenty of talk about reversing or lessening the symptoms of Rett, mainly because of a drug trial going on at the Boston Children's Hospital. I heard there was a study published a couple years ago talking about some promising results in mice that were given Rett Syndrome that lead up to the clinical trial, but it wasn't clear how promising the research was. I thought I'd heard that the hormone they were using was happened upon by accident, and they weren't even sure what its effects would be, so I decided to dig in and do a bunch of research of my own. This post is a place for me to collect my thoughts and summarize the findings I came across. Maybe it will be useful for someone else as well.

I started with what I understood was the Very Important Paper. I found a link to it on Wikipedia, so I knew it was a big deal :-). Actually there were a bunch of links to it, some of them related to the Boston study.

The Very Important Paper is titled Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice and was written in 2008. It starts by talking about how they've had a hard time finding exactly what things are downstream effects of the MeCP2 mutation that causes Rett, one that they have found is BDNF (brain-derived neurotrophic factor) regulation.

Before I keep going on that paper I had to switch to another paper, The Ups and Downs of BDNF in Rett Syndrome, since unlike the authors I didn't know anything about BDNF or how exactly Rett affects it (researching protip: "etiology" means the study of causation or origination). As explained in the second paper (something of a summary paper), the BDNF connection was first discovered in 2003. In something of a surprise, BDNF levels are actually lower than normal (this is the important part), in spite of the fact that the MeCP2 mutation causes BDNF repression to fail. In other words, MeCP2 normally helps keep BDNF levels in check, so it seems strange at first blush that an MeCP2 mutation would causes lower levels of BDNF instead of higher levels. It turns out that BDNF levels actually start out high for Rett mice and drop to lower levels some time after that. The paper never actually concludes why the levels drop, and I'm still digging for more studies on that, but at least I had what I needed on the relationship between BDNF and Rett.

Back to The Very Important Paper.

The paper continues by referencing another paper, The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression, that talks about how giving mice extra BDNF fixes a bunch of Rett symptoms including "locomotor activity levels". Unfortunately, BDNF doesn't cross the blood-brain barrier well, so it's hard to create a treatment using BDNF.

However. IGF-1 (Insulin-like Growth Factor 1, which incidentally is used by body builders) is a hormone that has a lot of the same results as BDNF, and is much better at crossing the blood-brain barrier. The point of this study was to try using IGF-1 as a treatment for mice with Rett.

The results were very positive. IGF-1-treated mice have a longer lifespan than untreated Rett mice, their physical activity is almost back in line with "normal" (they called them "wild-type") mice, and their breathing variability (Rett causes a lot of breathing irregularities, especially when sleeping) and heart rate (there's lots of weird heart problems related to Rett, e.g. Long QT Syndrome) are also improved.

Next came the really interesting stuff. Rett mice typically have less-heavy brains than normal mice, but when they were given IGF-1, brain weight also increased. That's very promising for something that is clearly a neurological disorder.

Rett is known to result in immature synapses in the brain. For a long time it was assumed that this was permanent, and that there would be no way to improve synapse development for girls with Rett should a cure ever be found. People assumed if a treatment were ever found, it would have to be given *before* Rett presented in order to do much good. (here are two sources for this statement -- though it's one I didn't find until later in my research)

However, as part of this study, the team tested "cortical plasticity" of MeCP2 mice. Plastic-what? Here's the deal: when you're young, your brain is pretty flexible and adjusts to changes very quickly. This is called "plasticity". As you get older and your brain is more developed, it can't adjust as quickly. So to study this, the researches recorded the eye dominance for a bunch of normal and MeCP2 mice. Then they stitched one of their eyes shut. Young mice should be able to adapt quickly to a change like that and shift eye dominance to the open eye, and old mice wouldn't adjust very well. Since Rett causes immature synaptic development, an old MeCP2 mouse should be more like a normal young mouse, and should be able to adjust quickly to the change. That's exactly what happened -- except for the mice that were given IGF-1. IGF-1-injected Rett mice responded like the normal old mice, which suggests that IGF-1 helps to "mature" brain synapses to more like what they're supposed to be.

Remember, that's a restoration. The immature synapses that are seen in Rett cases can actually be addressed, which means treatment can help existing Rett cases, not just brand new cases. This sounded like big news to me.

It was at this point that I started checking more sources, and came across more research. I thought the Very Important Paper was where they concluded that Rett symptoms could be reversed without permanent damage, but there were actually two prior studies that had already shown that: Reversal of neurological defects in a mouse model of Rett syndrome (full text not available) and Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2. Those two studies focused on actually restoring the MeCP2 deficiency itself. But getting exactly the right amount of MeCP2 is very difficult and potentially dangerous, which is why work is being done on things like BDNF and IGF-1, for example.

Anyway, this all led me back to the Boston study, which I now felt like I understood the reasoning for. I'll summarize according to my understanding now.

This is the new Rett dude at Boston Children's

Boston Children's Hospital's Rett Team is running a multi-phased clinical study of the effects of IGF-1 on girls with Rett Syndrome. The first phase of the study, why has already concluded, was focused on making sure there were no major negative side effects that came from giving girls the IGF-1 hormone. It was originally a 4-week study with 12 girls that, after it went well, was extended an extra 20 weeks in which time all the girls (even the control group from the 4-week study) were given IGF-1. I missed the webinar where they summarized the results, but it sounded like there were no major concerns. The only thing probably of note is that the study was limited to girls 12 and under, since there are concerns with regularly prescribing growth hormones to more matured individuals (but apparently a separate study for a different disorder is already investigating this, so they're waiting on the results of that study... I'll see if I can find a link and post it here).

Phase two of the study hasn't started quite yet (I think it got delayed after the Rett dude at Boston Children's ended up leaving for family issues), but should start relatively soon. I just got an email update on it via the private Rett mailing list, RettNet. The age limits were restricted to between 5 and 10 to try to get a more homogenous set. The goal with phase two is to actually examine and measure the results of regular IGF-1 intake on Rett symptoms (behavioral changes, motor impairments, seizures, breathing abnormalities, hand stereotypies, etc.). Once that's done, if it looks like it actually helps, they're hoping for a phase three, which would be a major stepping stone toward getting FDA approval of the drug for treatment of Rett.

Anyway, that's what I got out of the research I've done so far. I have more digging I want to do for sure.