Grace for Rett » Grace's Life with Rett Syndrome

Rett syndrome research :: NNZ-2566 in plain English

If you follow Rett research closely (or maybe even loosely), this will be a drug name you’re familiar with. My Google analytics tells me it’s one of the most popular searches currently bringing people to this blog so I know you’re out there and looking for information about this potentially groundbreaking new medication and the implications it may have for Rett syndrome.

NNZ-2566 is a medication being developed by the small pharma company Neuren. Neuren is a company in New Zealand which has offices in Australia and the United States. They have special interests in areas of neuroscience where there are gaps in development of treatments. Neuren currently has a growing portfolio on traumatic brain injury, neurodegenerative disorders and neurodevelopment disorders.

There are very few human clinical trials actually going on for Rett syndrome and NNZ-2566 is one of them. The trials are happening in America as we speak.


So the first question I aim to answer for you is “what is it?” We have a protein prevalent in our bodies called IGF-1. Its function is to help cells grow. It is an important component in the actions of the growth hormone in all of our bodies. In the brain, it helps cells to divide and make synaptic connections from neuron to neuron. However, people with Rett syndrome have issues with their IGF-1 because MeCP2 affects its expression. Now, where NNZ-2566 comes into this mix is this: by looking at the IGF-1 protein and which bits of the whole package could be beneficial in treating Rett, scientists have found that the first 3 amino acids of IGF-1 are what’s needed.

IGF-1 does not readily pass from our circulation into the brain. However, a small piece of IGF-1, called a tripeptide, is able to pass from the blood and into the brain. NNZ-2566 is a synthetic version of the tripeptide that has been modified so that it can be absorbed orally, passing from the digestive tract into the circulation and then into the brain.  Evidence from the laboratory suggests that the tripeptide is the part of IGF-1 that seems to be effective in treating Rett syndrome. A trial of NNZ-2566 is underway in adolescents and adults with Rett Syndrome at Baylor College of Medicine and the University of Alabama. A trial of IGF-1 in young girls is underway at Boston Children’s Hospital.


NNZ-2566 is delivered as an oral, strawberry flavored liquid whereas IGF-1 has to be injected.


Just like any drug, IGF-1 isn’t suitable for everyone. When growth hormones are given after puberty, they can cause continued bone growth so there’s a window of time when this could be administered as a treatment. However, NNZ-2566, which is a peptide and not the whole protein, does not appear to have those same issues. The clinical trial with NNZ-2566 is designed to show that it is suitable for teenagers and adults with Rett. This means NNZ-2566 could have the potential to be suitable for anyone with Rett at any period of their life, something that no other suggested treatment we’ve ever seen can claim.

[The Benefits]

NNZ-2566 is an easy, strawberry flavoured liquid that crosses the brain/blood barrier.

You may remember a while back, I posted about gene therapy and the post said that, while treatment with vectors is an interesting idea, there are great challenges. That these methods were like using a shotgun when what we need is a sniper rifle.

Well, IGF-1 is like a sniper rifle. Through the current trials, scientists are hoping to deliver more growth enhancers into the central nervous system which gets right to the central problem immediately, bypassing the need to deliver a new gene with a vector and hope it is expressed to correct the defective MeCP2.

But of course, I’ve already mentioned that IGF-1 needs to be injected while NNZ-2566 is an oral medication to hopefully deliver the exact same results and be potentially suitable for  any age.

[The Challenges]

Like every current suggested method for the treatment of Rett, there are a few challenges to face.  The fundamental challenge with NNZ-2566 is that it is new drug, and new drugs have to go through a lot of rigorous testing before they can be used on all age groups.  Since NNZ-2566 was developed by Neuren for traumatic brain injury, it has had a sizable amount of safety testing already completed and has been shown to be generally safe and well tolerated by adult human subjects. However, this fact does not remove the need for safety evaluation in Rett patients.

[Current Studies]

NNZ-2566 is currently being studied in human clinical trials for both Rett syndrome and traumatic brain injury. Both conditions have something in common in that there are weak synapses in the brain. A study in Fragile X syndrome is scheduled to begin shortly.

Phase 1 (the safety tests) have been completed. We know that it’s a well-tolerated drug.

Phase 2A began in May 2013 and hopes to end in September this year. These are currently being undertaken at Baylor College of Medicine with Drs. Dan Glaze and Jeff Neul and at the University of Alabama – Birmingham with Dr. Alan Percy. This trial consists of 60 participants between the ages of 16-45.

The Phase 2 study examines the safety profile, looking for unexpected adverse changes, deterioration or anything that wouldn’t be expected in the natural progression of Rett syndrome. This is where the ongoing Natural History Study adds value. Unless we study Rett in the long run and learn what happens and the effects we can expect, it’s difficult to measure the effectiveness of drugs we want to trial for Rett. The data extracted during the Natural History Study gives us baselines of what to expect so that during these types of trials, we can know what would normally have been expected and gives scientists a greater base of knowledge for use when monitoring such trials.

This phase is also measuring efficacy (effectiveness).

Based on the tests with mouse models, we’re hoping to see improvements in breathing and cardiac function, and decreases in seizures. The patients are also being observed for changes in many other behaviors.

[The Next Step]

The next step for NNZ-2566 will be proof of concept studies in the pediatric population. Remember, the youngest person in the current study is 16 years old because the FDA guidelines are such that a drug usually cannot be tested on juveniles until the trial has first been successful with adults (when adult patients are available).


This is where partnerships are incredibly important. IRSF started the Baylor study with a $600,000 ANGEL grant to get it going, but this doesn’t even come close to covering the cost. Partnership with Neuren is extremely important to bring more resources to the table for these trials.

[Considering a Trial?]

It’s very important to fully understand the implications of putting your child into a clinical trial. Please view this document from IRSF on safety in Rett Syndrome trials.

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
  • Nancy Jones, Ph. D. - Senior Director, Clinical Development and Medical Affairs at Neuren Pharmaceuticals

Heather Clark - April 19, 2014 - 2:25 am

Wow sounds exciting to see all results and see how the girls do long term:)

Bev Glaus - April 21, 2014 - 1:36 pm

Hi Jill..very interesting ..keep our fingers crossed Dad

Linda Alvarez - April 22, 2014 - 4:09 am

So many scientists are hopeful that our girls can be helped and live near normal lives within the next decade,,,,Every time I see one of our kiddos contributing their time and energy being an ambassador to get the word out about Rett’s and to bring science one step closer to the cure, I think to myself,” Natalie, look what you (and your family) have to done to CHANGE THE WORLD! You can’t speak or move, and you may be one of the people who open up a whole new scientific protocol to allow MILLIONS of people a better quality of life!” Natters, you are a HERO! I look up to you, Girl! Even if technically you are my baby girl. You are doing something heroic for humankind! Most of us can’t claim that, Sweetheart! You’re doing good work! Proud of you!

Teresa McLoud Bower - April 22, 2014 - 5:49 am

I am excited to see the out come of all the testing they have done. Our kiddos need a cure.

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

Eye tracking tests – Rett vs. Autism

Note: there is video in this post. If you’re reading in your inbox or RSS, click here.

In October at the European Rett Syndrome Conference, one presenter showed a very interesting study which tracked the eyes of typical children, children with rett and those with autism (ASD). The differences in what they were looking at on the same image were striking. The autistic children looked at the corners of the image and at the inanimate objects (like a clock) and the kids with Rett looked straight into the eyes of the people on the images, even more intensively than the typical children.

Find the image below and below that, an intersting talk from a doctor who has been using eye tracking to diagnose autism in babies.

Medical Research: Discovery, Translational, Clinical [in plain English]

by Elizabeth Halford, with contributions from Steve Kaminsky, Ph.DJanice Ascano, Ph.D., Paige Nues and Kori Coates.

There are three streams of scientific research into Rett syndrome: discovery based research, treatment (“translational”) based research and clinical research. IRSF have an ongoing study into Rett syndrome via their Natural History Study which is a fantastic form of clinical research. We’d love to show you a video about it today, but first…


So now you’re probably thinking “what’s the difference between discovery and treatment based research?” Here’s what the IRSF’s Chief Science Officer, Steve Kaminsky, PhD had to say when we asked him the same question:

Discovery Based Research is focused on developing or proving a concept, while translational (treatment) based research is focused on putting a proof of concept into practice.

A simple analogy may help: discovery based research proved that a round object helped in moving heavy objects that could not be carried, while translational (treatment) based research demonstrated that wheels with axles were more efficient than rollers in moving heavy objects.

How about a medical analogy:  It was discovery based research that showed that AIDS was caused by a virus.  It was translational (treatment) based research that showed that a combination of drugs could slow down or halt the replication of the AIDS virus.

Now let’s apply this analogy to Rett syndrome:  In 1999 it was discovery based research that illustrated that MECP2 mutations were associated with Rett syndrome.  It is translational (treatment) based research that has shown what MeCP2 does so that specific therpaies can be developed.

Additionally, there’s another form of research taking the information learned from discovery and the practice created by the translational into something to actually test on patients with Rett. This is called clinical research. Again, in the words of Steve Kaminsky, “clinical research involves research conducted with human subjects and can include the use of new translational tools (molecular, chemical, or physical) directly with the patient.” Clinical research is taking the translational research findings and applying them to the actual people suffering from Rett.  Taking it out of the laboratory and into the clinic for our girls.  Clinical trials, such as IGF-1 and NNZ-2566, are this leap. But there’s one important pre-cursor to all clinical trials.  That is the clinical research that maps the course of the disorder so we know exactly what we’re looking to improve.  And this is where IRSF’s Natural History Study slots in to this picture.

See, we know that a MECP2 mutation or deletion can result in Rett syndrome, but we still have not truly and completely documented in a scientifically rigorous manner exactly what Rett syndrome is!  And that is our necessary clinical research, to benchmark for real change/improvement off of a clinical trial.  We as parents don’t even really know what Rett syndrome is, although we certainly know what it is not for our individual child.  Rett syndrome does not talk, walk, or eat easily, and sometimes it sleeps well, and sometimes it has seizures and sometimes it does not.  All of these “sometimes” become problematic for clinical trials, so the Natural History Study tightens that “sometimes” or “maybe” into a more solid “usually”.

The Natural History Study is not about clinical research using interventional treatment methods.  It is about making observations directly of the patients over time as new care is being developed. Why is this important?  A natural history study is the single best avenue to study the hallmarks of Rett and how these hallmarks progress over time. The fact that an isolated population can be followed in depth by the same group of medical specialists will unfold the obvious and subtle traits of Rett. Observing these traits over time gives rise to ways and ideas to address the biology associated with Rett.  Since the traits of Rett patients can differ from patient to patient, these in depth studies start to unfold patterns that otherwise would go unnoticed.

There is a great need for these different forms of research into Rett syndrome. While there may be a one-stop-shop reversal/cure out there, we also need to be gaining a better understanding about the condition. Rett syndrome is a very young diagnosis. It was only in 1966 that Dr. Andreas Rett first published a description of the syndrome to be named after him. And in 1999, the gene was found by Huda Zoghbi’s team to show what actually caused Rett syndrome. In the scientific world, 10 years is a very short time. Scientific research is a painstakingly careful and long process, especially for those so desperately wanting the results in their lifetime.

Is there going to be a cure for Rett syndrome? Of course! Absolutely! It’s out there somewhere. But I also believe it would be nearsighted to focus only on research into complete reversal or recovery. While there may be a genetic based therapy in our future, there is an immediate need to be gaining a better understanding about this condition to aid in treating all Rett patients at various age and stages of health. This quote from Steve Kaminsky sums it up perfectly:


The Natural History Study is part of this journey. Please watch this video to learn more.

F a c e b o o k