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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

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Do superhumans actually exist? Apparently they do, and their DNA could hold the key to solving some of the world’s health problems.

Freakishly strong bones and an alarmingly high pain threshold aren’t the result of falling in a vat of toxic waste, they are caused by genetic mutations. Pharmaceutical companies have not only taken notice, but are investing heavily to produce treatments for a variety of disease indications that could have annual revenue in the billions.

If someone with brittle bones or severe pain can get relief in a pill or an injection, could there be a cure for Rett and other MECP2 disorder unknowingly hidden in someone’s DNA? Twenty years ago, when sequencing DNA took decades and billions of dollars, getting to the answer would have been technologically impossible. But today it’s more than feasible. RSRT is funding several projects in the lab of Monica Justice and Jeffrey Neul aimed at identifying mutations in other genes that make an MECP2 mutation less severe.

Bloomberg Business covered this amazing topic with some great illustrations from Stephanie Davidson.

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In March of this year, the lab of Michael Greenberg at Harvard Medical School published data showing that the MECP2 gene lowers the expression of genes that are physically long.The scientists found that the MeCP2 protein acts as a dimmer switch, dampening the expression of long genes. When the MeCP2 protein is absent, as in the case of Rett, with no dimmer switch to regulate it, long gene expression goes up. This work suggests that drugs that can rebalance the expression of long genes might have therapeutic benefit in Rett.

Mark Zylka from the University of North Carolina at Chapel Hill, working independently on a non-Rett project, discovered that a class of drugs called topoisomerase inhibitors reduces the expression of long genes. Almost by accident, this raised the possibility that this class of drugs could be clinically relevant for Rett. One such drug is topotecan which is FDA approved for cancer. The Greenberg lab is now testing Topotecan in Rett mice models.

However, Topotecan may not be the ideal drug since it doesn’t get into the brain easily and would be toxic for long term use. As a result, RSRT has awarded Mark Zylka $400,000 to screen for other compounds that can rebalance expression of long genes safely.

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It’s an exciting time for gene therapy with a myriad of disease indications being explored ranging from blindness to potential cures for HIV and successful clinical trials being conducted for infants with Spinal Muscular Atrophy (SMA). These awesome advances have not been ignored by RSRT which is why we recently launched a Gene Therapy Consortium (GTC) that is undertaking key experiments to determine if this approach is a feasible strategy for Rett. Program Director, Tim Freeman had a chance to sit in on a GTC meeting in Boston recently and shared his perspective in this post.

Gene therapy in the traditional sense delivers healthy genes into the body by way of a vector (Trojan horse) to compensate for mutated genes. But what if you could repair a gene by splicing out the mutation with “molecular scissors” and replacing it with the correct bits of DNA? Genome editing, as it’s called, is sounding less like futuristic science fiction and more like a tangible treatment.

A revolutionary new technology, Crispr-Cas9, which capitalizes on a naturally occurring molecular phenomenon allows for the mutated bits of DNA to be snipped out and the correct bits to be inserted. While this technology is not yet ready for prime-time there is lots of research taking place and progress is quick-paced.

What if you could go right to the root cause of that disease and repair the broken gene? That’s what people are excited about,”

– Katrine Bosley, Editas Medicine

We encourage you to read this Wall Street Journal article to learn more about Crispr-Cas9.