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By Delthia Ricks
delthia.ricks@newsday.com

Long Island scientists have moved a tantalizing step forward in efforts to better understand — and alleviate — some of the devastating symptoms of Rett Syndrome, a rare, incurable, neurodevelopmental condition that primarily strikes girls.
The syndrome shares key symptoms associated with autism spectrum disorders but has many symptoms that are unique, including an underlying genetic mutation, said biochemist Nicholas Tonks of Cold Spring Harbor Laboratory.

Writing in the current issue of the Journal of Clinical Investigation, Tonks and colleagues report on a possible — but still distant — drug intervention.

“When you do classical academic research that has the opportunity to help real patients, it’s a reason to get out of bed in the morning,” Tonks said. “It is a very exciting time.”

Tonks and research associate Navasona Krishnan have found that their so-called small-molecule — an experimental drug candidate — extends life expectancy in mouse models bred to develop Rett Syndrome. Tonks hopes eventually to move forward with human clinical trials of the approach. Currently, there are no drugs available to address symptoms associated with the neurodevelopmental disorder.

Tonks’ strategy involves inhibiting the activity of an enzyme called PTP1B, which he discovered a 25 years ago. The enzyme goes awry in Rett Syndrome, as it does in certain cancers and some metabolic disorders. Controlling it, he and his team found, relieved syndrome-related symptoms in the humanized mice.

Tonks and colleagues found, for example, that PTP1B levels are extremely high in the afflicted mice. But when the enzyme was inhibited, cell communication processes flowed normally.

Now, he wants to know whether inhibition with his candidate molecule will do the same in people and is collaborating with scientists at Case Western Reserve University in Cleveland.

Rett Syndrome usually appears in toddlers after a normal period of development during infancy. Scientists have found that mutations in the MECP2 gene, which resides on the X chromosome, cause the condition.
Because males with Rett Syndrome have only one X chromosome, they usually die as infants. Females with the syndrome, however, can survive into middle age, experts say.

But afflicted girls and women have a constellation of problems: breathing difficulties, Parkinson’s-like tremors, small head size, mental retardation, poor muscle development and an inability to speak. People with Rett Syndrome require lifelong, round-the-clock care.

Advocates for children and adults with the syndrome call it the most physically disabling of disorders linked to the autism spectrum.

“Historically it was considered an autism spectrum disorder,” said Monica Coenraads, executive director the Rett Syndrome Research Trust in Connecticut and the mother of an 18-year-old daughter with the syndrome.

“Now that there is a gene associated with it, it’s no longer included in the DSM-V,” Coenraads said of the Diagnostic and Statistical Manual, Fifth Edition. The volume is considered the bible of psychiatry.

Nevertheless, she added, many people still refer to Rett Syndrome as an autism spectrum disorder. An estimated 16,000 people are affected in this country, with 350,000 worldwide.

Dr. David Katz, professor of neurosciences and psychiatry in the School of Medicine at Case Western, said the work at Cold Spring Harbor Laboratory is on an intriguing track. “These are promising results, encouraging results,” said Katz, who has studied Rett Syndrome for years. “This is what we call early stage findings where there are encouraging results in a mouse model.”

What has yet to be discovered, Katz said, is whether the experimental drug candidate can be given over a long period of time. It also is important to know whether there are side effects or other safety concerns.

Katz added that other laboratories in this country and abroad are investigating additional possible strategies.
Coenraads welcomes Tonks’ work as well as that by other scientists.

“It’s a very exciting time,” she said of the collective Rett syndrome research. “We are very optimistic.”

*Sourced from Newsday.com

In contrast to the leadership of most organizations we yearn for the day when RSRT is no longer in business – that will mean an end to Rett. Until that day comes we will continue to invest in high quality science. In the first half of 2013 RSRT has committed $1.7 million to new projects that range from basic science to clinical trials. We invite you to learn about our investments, which our donors have made possible. As always we welcome your questions and feedback.

Copaxone Clinical Trials

There is a multitude of data suggesting that mice models of Rett have low levels of a neurotrophic factor called BDNF (brain derived neurotrophic factor). BDNF is a very important and complex protein that is implicated in a variety of disorders. Increasing BDNF in the Rett mice models, either genetically or pharmacologically is beneficial. An FDA approved drug for multiple sclerosis called copaxone (or Glatiramer Acetate) is known for increasing BDNF and therefore of interest in treating Rett.

RSRT has committed to funding an open label study of copaxone in two centers, the Tri-State Rett Syndrome Center at Children’s Hospital at Montefiore in the Bronx, under the supervision of Dr. Sasha Djukic, and at Sheba Medical Center in Ramat Gan in Israel under the supervision of Dr. Bruria Ben Zeev. Each center will give copaxone to ten individuals for 6 months. Below is a comparison of the two studies. 

Sasha Djukic, M.D., Ph.D.

Sasha Djukic, M.D., Ph.D.

Bruria Ben Zeev, M.D.

Bruria Ben Zeev, M.D.

USA Israel
Title Pharmacological treatment of Rett Syndrome with Glatiramer Acetate (Copaxone) An open-label exploratory study to investigate the treatment effect of glatiramer acetate (Copaxone) on girls with Rett Syndrome
Principal Investigator Aleksandra Djukic, MD, PhD Bruria Ben Zeev, MD
Location Children’s Hospital at Montefiore, Bronx Sheba Medical Center, Ramat Gan, Israel
Objectives Primary: gaitSecondary: cognition, autonomic function, EEG, quality of life Primary: EEG improvementSecondary: autonomic function, general behavior, communication, hand stereotyping, feeding, gastrointestinal
Study Size 10 girls – 10 yrs old and up 10 girls – 6 to 15 yrs old
Dose (injections) Ramp up to 20 mg per day Ramp up to 20 mg per day
Length of study 6 months 6 months

While copaxone is not going to cure Rett Syndrome we hope that by increasing BDNF we will see improvements in symptoms. The trials are currently recruiting.

The X Factor

If you’ve been following RSRT’s activities then you know that one of the strategies we are pursuing is reactivation of the silent MECP2. We are adding Michael Green of UMass to our existing portfolio of labs who are working in this space.

Michael Green, M.D., Ph.D.

Michael Green, M.D., Ph.D.

Dr. Green is taking a somewhat unconventional approach as he is attempting to reactivate the entire X chromosome and not just MECP2. His work first came to RSRT’s attention in 2009. We learned that he was conducting a screen to identify genes that control X chromosome inactivation (XCI). As his work matured over the next few years he did indeed identify factors that control XCI, some of which belong to molecular pathways for which there are drugs. These drugs can now be tested in culture and in vivo in the Rett mice models.

Recently a paper from a colleague of Michael Green’s, Jeanne Lawrence, received enormous attention for doing the opposite of what Dr. Green proposes – inactivating the extra copy of chromosome 21 that causes Downs Syndrome (DS). While this work is not ready for prime time it is an exciting new avenue that could eventually make treatment for DS a reality.

Continuing our X Factor focus we awarded an additional grant to Jeannie Lee of Harvard University. She is currently funded for a drug screen to reactivate MECP2. While the goal of the new award is the same – activate MECP2 – how she proposes to accomplish it is completely novel.

Jeannie Lee, Ph.D. at an RSRT meeting in November

Jeannie Lee, Ph.D. at an
RSRT meeting in November

The hypothesis of Dr. Lee’s approach rests on an observation that a group of proteins called Polycomb complexes working in concert with a certain type of RNA, called noncoding RNA (lncRNA) are relevant for keeping genes silent on the inactive X.

Dr. Lee’s therapeutic strategy is to awaken the MECP2 gene by disrupting the binding that occurs between the lncRNA and the Polycomb complexes.

While the work is early stage, if Dr. Lee’s hypothesis proves correct this approach would be attractive.

Ketamine – the follow up

Last October David Katz of Case Western Reserve University published a paper showing that certain physiological symptoms in the Rett mice normalized after treatment with an aesthetic called ketamine. With RSRT funding Dr. Katz will continue to pursue this line of exploration with additional drugs that work in the same pathway but have less side effects. He will also attempt combination therapies with various drugs.

Below is a video interview with Dr. Katz that was posted earlier this year.

Gene Therapy for the MECP2 Duplication Syndrome
Kevin Foust (left) and Brian Kaspar at a recent RSRT meeting.

Kevin Foust (left) and Brian Kaspar
at a recent RSRT meeting.

The final award was granted to Kevin Foust of Ohio State University. Dr. Foust has been working with Brian Kaspar and Gail Mandel on gene therapy approaches to treat Rett Syndrome. This award builds on that work by extending a gene therapy approach to the MECP2 Duplication Syndrome. Dr. Foust will deliver RNA interference (RNAi), a biological process in which RNA inhibits protein production) via a vector in duplication syndrome mice.

If the data is encouraging this work would form the basis for a therapeutic approach to treating patients.

This work is being funded via the MECP2 Duplication Syndrome Fund at RSRT and directly supported through the efforts of the duplication families.

We look forward to bringing you updates on these and all of our projects.  Once again we thank all of our supporters – this is your money at work for our girls.

RETT SYNDROME RESEARCH TRUST WEBSITE

by Kelly Rae Chi

In September of 2011, RSRT met with the National Institute of Neurological Disorders (NINDS) and other public and private organizations that fund Rett Syndrome research to discuss crucial knowledge gaps in the field. The main findings of the workshop were published recently in Disease Models & Mechanisms.

In particular, the meeting focused on how the research community can improve its chances of success in clinical trials. Preclinical studies require a huge investment of time and effort studying disease in rodent models. Even then, for a variety of reasons, drugs that show promise in preclinical studies will often fail in the clinic.

Here are a few big hurdles in preclinical animal studies — some that are specific to Rett research — and how experts are meeting those challenges.

1. Studying female mouse models of Rett.

“It’s important that when we do a drug trial, that we really impact features that are clinically meaningful, features that are going to impact patients,” Huda Zoghbi of the Baylor College of Medicine in Houston, Texas, told RSRT in a recent interview.

Like girls with Rett, however, female mouse models of the disorder vary in the type and severity of their symptoms, which makes them harder to study than males.

That’s because the gene missing or mutated in Rett, MECP2, is located on the X chromosome.  Female mice — which, like girls, have two X chromosomes, only one of which is active — will have either mutated protein or normal protein levels, depending on which copy is expressed in the cell. Rarely are they missing all of their MeCP2 protein.

In contrast, male mouse models missing the Rett gene have no protein at all. Although these mice have paved the way in understanding the protein’s role in the brain, when it comes to treating Rett, results from studies of male mouse models may not be the ideal model to work with.

More researchers are turning to female mouse models. Zoghbi and Rodney Samaco, also at Baylor, for example, published a study in October in Human Molecular Genetics, describing two different female mouse models of Rett in detail. Detailed characterization of these mice will help lay the groundwork for preclinical studies.

2. Unknowns about how an animal’s environment affects therapeutic efficacy.

No two research labs are alike. The ways in which they differ, including animals’ access to food, housing, lighting or other environmental factors, might well influence an animal’s response to a drug.

What’s more, an individual mouse’s genetic environment — meaning the genetic background on which Rett mutations are made — affects some of its symptoms, such as obesity and abnormalities in social behavior. These genetic differences may also affect how animals respond to treatment.

Variability in genetic and environmental conditions plague scientists studying many conditions, not just Rett syndrome. One way to help address this obstacle, according to Rett researchers in the Disease Models & Mechanisms workshop summary, is to study symptoms and potential therapies across a variety of models and in many lab settings. Those mouse models that show consistent results across different environments will be most useful for translational studies.

3.  Recapitulating speech problems in mice.

Of the many symptoms seen in Rett, loss of speech is among the most challenging to study in a mouse model. Some groups have shown that Rett mouse pups produce unusual vocalizations when they’re separated from their mothers in early postnatal life. These sounds are either more or less frequent than in healthy controls, depending on the mouse model studied. Future work will need to sort out these conflicting results and identify a mouse model that best captures this hallmark symptom of Rett, researchers say.

4. Avoiding bias, which can prevent preclinical errors.

Unintended biases can creep into animal studies. This can lead researchers to conclude a treatment is effective when it isn’t, or it can cause overestimations of a drug’s efficacy.

In recent years, researchers across numerous fields have stepped up efforts to improve study rigor. In June of this year, NINDS convened a panel of scientists, funders and journal editors to talk about how researchers can do a better job reporting methods in preclinical animal studies; both in grant applications and journal publications. At the very least, the panel concluded in a perspective published October in Nature, researchers should report on the following practices:

  • Randomization, where animals are randomly assigned to receive either treatment or placebo;
  • Blinding, where researchers doing the experiments or analyzing the data are unaware of whether of which animals are receiving treatment or placebo;
  • Sample-size estimation, a calculation of an appropriate sample size at the study’s outset;
  • And how data is handled, for example, deciding on study’s primary endpoints, or how to handle missing data points or outliers, before starting the study.

Not reporting such details has, in the past, been linked to overestimations of therapeutic efficacy, according to the NINDS report.

Now Rett researchers have added their voices to the mix in the Disease Models & Mechanisms report, voicing their support of NINDS’s recommendations and emphasizing the need for rigorous experimental design.