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A paper authored by Huda Zoghbi and Jianrong Tang at Baylor College of Medicine and published in Nature describes improvement in learning and memory paradigms in mice models of Rett after deep brain stimulation (DBS).  This research was funded, in part, by RSRT.

DBS is a surgical procedure that involves implanting electrodes in specific areas of the brain. The electrodes are attached to a pacemaker-like device placed under the skin in your upper chest that generated electrical impulses.

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The disorders most commonly treated with DBS include Parkinson’s disease, essential tremor and dystonia. The procedure is also being studied as a treatment for epilepsy, cluster headaches, Tourette syndrome, chronic pain and depression.

While the procedure looks daunting neurosurgeons view it as rather routine. 

Here is a remarkable video showing DBS surgery for a violinist who was having difficulty playing due to  tremors. 

 

The experiments conducted at Baylor targeted a brain region called the fornix. While improvements were seen in learning and memory no changes were observed in other symptoms such as anxiety, motor coordination, social behavior, body weight. It will now be important to see whether targeting other brain regions via DBS will result in improvements in these symptoms.

Below is a podcast between Dr. Zoghbi, Dr. Tang and the RSRT Executive Director, Monica Coenraads. The scientists describe the highlights of their experiments and key next steps. 

Urology

 

Later this month, from the 17th to the 21st, about 30,000 neuroscientists will gather in Chicago for the annual meeting of the Society for Neuroscience. There will be about 40 presentations on Rett Syndrome. Most are basic science oriented but one with clinical relevance caught our attention.

We often hear of parents being concerned because their daughters are not urinating as normal on a particular day or two. Turns out this is not unusual in Rett. Dr. Jeff Neul, formerly of Baylor and now at UCSD, found that individuals with Rett often suffer from urological dysfunction including frequent urinary tract infections, kidney stones, and urine retention. He also found urological problems in the Rett mice.


Loss of MeCP2 causes urological dysfunction and contributes to death by kidney failure in mouse models of Rett Syndrome
C. S. Ward, T.W. Huang J. Herrera, R. C. Samaco, M. Pitcher, J. L. Neul

Rett Syndrome (RTT) is a neurodevelopment disorder characterized by loss of acquired skills during development, autonomic dysfunction, and an increased risk for premature lethality. Clinical experience identified a subset of individuals with RTT that present with urological dysfunction including individuals with frequent urinary tract infections, kidney stones, and urine retention requiring frequent catheterization for bladder voiding. To determine if urological dysfunction is a feature of RTT, we queried the Rett Syndrome Natural History Study, a repository of clinical data from over 1000 individuals with RTT and found multiple instances of urological dysfunction. We then evaluated urological function in a mouse model of RTT and found an abnormal pattern of micturition. Both male and female mice possessing Mecp2 mutations show a decrease in urine output per micturition event. Furthermore, we identified signs of kidney failure secondary to urethral obstruction. Although genetic strain background significantly affects both survival and penetrance of the urethral obstruction phenotype, survival and penetrance of urethral obstruction do not directly correlate. We have identified an additional phenotype caused by loss of MeCP2, urological dysfunction. Furthermore, we urge caution in the interpretation of survival data as an endpoint in preclinical studies, especially where causes of mortality are poorly characterized.


 

Fyi, micturition describes fainting shortly after or during urination. It is a type of Vasovagal response.

Housed in the nucleus of every cell in the body is 6 feet of DNA.  The nucleus is so small that 10,000 of them with a combined total of 11 miles of DNA would fit on the tip of a needle.  The video below explains how the unimaginable feat of coiling this amount of DNA is accomplished.

 

Today the journal, Cell, published research from the lab of Gail Mandel showing that the Rett protein, MeCP2, plays a role in how DNA is packaged into the nucleus. This research was funded, in part, by RSRT through the MECP2 Consortium. Using a technology called array tomography the Mandel lab found that in cells that are missing MeCP2 the DNA is more tightly compacted.

Increased compaction “hides” genes from the cellular machinery needed for protein production. So genes that are compacted are less likely to be producing protein.

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Imagine DNA as a slinky with genes along the coils. In a compressed state it is difficult for these genes to be accessed by the necessary molecules that facilitate protein production.

 

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However when the slinky is stretched out the genes become very accessible for protein production.

 

 

The scientists also found that the degree of DNA compaction was correlated to the degree of MeCP2 requirement in a given cell type. For example, cells that typically require large amounts of MeCP2 (eg. Purkinje cells) will suffer a greater change in compaction when MeCP2 is missing than cells who normally have a smaller requirement of MeCP2 (eg. astrocytes).

The video below shows normal nuclear compaction in Purkinje cells of female mice on the left and Rett mutant mice on the right.

The person responsible for this work, Mike Linhoff of the Mandel lab, describes the video, “The white shows DNA, while the green shows DNA sequences where MeCP2 binds. Red shows a particular protein modification that promotes DNA compaction. In the absence of MeCP2 this compacting modification invades the DNA sequences where MeCP2 usually binds.”

“The clinical relevance of the work is to point towards cures that will take into account neuronal-specific effects of MeCP2 loss. Once such strategy, which RSRT is already pursuing, is to reactivate the silent MECP2 on the inactive X. Other strategies might include identifying factors that can titrate gene therapy levels of MeCP2 in different neuronal types, or identifying a druggable common downstream consequence that occurs in all neuronal types,” shares Gail Mandel.

 

 

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Work from a variety of labs has identified the excitatory NMDA receptor as a possible target for intervention in Rett. The NMDA receptor is made of various components, including GluN2B and GluN2A. In previous work, Dr. Michela Fagiolini found that decreasing the activity of GluN2A rescues certain neuronal defects and symptoms. Furthermore, past studies identified age and region dependent abnormalities in the NMDA receptor system in young girls with Rett. Together these findings raise the possibility that administration of NMDA receptor modulators may improve Rett symptoms.

Another drug that blocks the NMDA receptor is ketamine.  Several years ago Dr. David Katz showed that low-dose ketamine treatment reversed deficits in brain activity in mouse models of Rett Syndrome in conjunction with significant improvements in neurological function, including breathing. Ketamine, historically used for sedation and anesthesia, has recently generated much enthusiasm for its ability to rapidly reverse major depression at low, sub-anesthetic, doses.  Last year RSRT awarded $1.5 million ($1.3 million + an additional $200K) in support of a Phase 2 clinical trial of low-dose ketamine for the treatment of Rett Syndrome. This trial will determine the effect of single doses of low-dose ketamine on breathing abnormalities and other Rett Syndrome symptoms.The study is being led by Dr. Katz and Dr. Daniel I. Sessler,  at the Cleveland Clinic. The trial will be recruiting patients shortly.

Dr. Fagiolini’s lab recently also began testing ketamine and found that chronic treatment significantly improves symptoms and extends lifespan in mice. Ketamine however can cause psychiatric side effects such as hallucinations. While the dosages used in Rett will be very small and below what should cause problems it is nevertheless prudent to explore other potential ketamine-like drugs in parallel.

The new funding to the Fagiolini laboratory will allow testing of two novel and selective GluN2 modulators.

I often come across statements to this effect, “The pharmaceutical industry is not interested in pursuing drug development for Rett Syndrome because the disorder is rare and companies won’t make any money.”

And yet, I am fielding emails, calls and in-person meetings with industry executives almost on a daily basis. From my perspective, Rett is clearly on the industry’s collective radar. This goes for both large pharmaceutical companies and smaller biotech firms, but why?

Industry is flocking to rare diseases and here are some of the reasons why:

  1. The biology of rare diseases is often better understood than that of common diseases. This is certainly the case with Rett because it is caused by a mutation in a single gene that has already been pinpointed.
  2. The US Orphan Drug Act, created to facilitate the development of drugs for rare diseases, provides companies with tax credits, funding grants for clinical trials, a waiver of FDA fees and 7-year market exclusivity.
  3. Rare disease drugs can demand hefty price tags. Annual costs of $100K to $500K are not unusual.
  4. Rare disease drugs have reduced marketing costs and often increased reimbursement possibilities.
  5. Clinical trials are much smaller therefore cheaper, and enthusiastic patient population often makes for easier trial recruitment.
  6. Drugs designed to treat rare disorders sometimes prove to be beneficial for a broader patient group.

Companies like Genzyme, Shire, Vertex, Alexion, BioMarin, Celgene and Aegerion just to name a few, have firmly established a successful business model for rare disease drug development.

This paradigm shift is good news for Rett. In addition to the above perks Rett offers a unique advantage that has not gone unnoticed by industry executives: reversibility!

While it’s extremely gratifying to witness this activity we must not let up on the intensity with which we support and drive basic science and clinical research. Industry’s interest in the therapeutic approaches that RSRT has been pursuing (activating the silent MECP2, modifier genes, downstream targets such as NMDA pathways, gene therapy) validates our research strategy. Our research has fueled a rich pipeline of potential drug targets and it’s imperative to keep that pipeline flowing.

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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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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.

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Dear Friends,

I had a remarkable experience recently at an all-day meeting in Boston with Monica and the scientists of RSRT’s Gene Therapy Consortium that I wanted to share.

The Consortium is a collaboration of four labs that are developing a way to use gene therapy to treat or maybe even reverse Rett symptoms. I certainly wasn’t expecting to add anything to the conversation at this meeting, and truth be told I was a little nervous about being there. I’m a parent, not a scientist, and here I was going to a meeting with some of the world’s leading gene therapy experts. This was going to be a far cry from tenth-grade biology class, which was a long time ago. I went to the meeting to be a fly on the wall, learn what I could, and try to get a big-picture sense of progress. It turned out I got all this, but I also got much more.

It was amazing and even moving to see these scientists talking so enthusiastically about gene therapy as a potential way to treat or cure our daughters. It’s one thing to read about these projects; it’s quite another to be there and see ten scientists (the four principal scientists brought lab members with them) discussing and sharing their progress. I was struck by how the Consortium is a true collaboration. These scientists were sharing ideas and resources freely, and I know they returned to their labs with critical new information. Something else that surprised me was their compassion. Maybe I was expecting a sort of detached scientific approach from them. But that’s not at all what I saw. The Consortium members care deeply about their work and the impact it will have on those with Rett. They are constantly thinking about the details of gene therapy of course—the over-and under-expression of genes, DNA packaging, and vector optimization (a vector is the vehicle or “Trojan Horse” that carries a healthy gene to a mutated cell)—but it’s all driven by a desire to change lives. This was wonderful to see. We have Monica to thank for propelling these and other scientists to care about outcomes for our daughters as much as she and all of us parents do.

It was also clear at this meeting that meaningful progress was being made. I’ve learned enough about gene therapy to understand that the vectors that Consortium members are developing are critical. An effective vector will need to deliver just the right amount and parts of a gene, which is much easier said than done. At the meeting one of the Consortium scientists presented data on a vector tested in mouse models that looks promising. While this is very good progress, a lot more research lies ahead. Using gene therapy to treat Rett remains theoretical until the Gene Therapy Consortium members prove otherwise.

Science is complex and I know sometimes it’s hard to envision exactly how funding for it is used. At this meeting I had an acute sense of how every dollar contributed to RSRT matters—what I watched unfold that day simply would not have happened without the generosity of many people. It was another reminder of how grateful I am to everyone who supports RSRT. I feel lucky to have been there and to have had the chance to literally watch progress being made. The meeting renewed my excitement about the future for my daughter and all the other girls and women I’ve met with Rett Syndrome.

Tim Freeman

Neurolixis

RSRT recently awarded $530,000 to Neurolixis, a small biotech firm in southern California that is developing the drug, NLX-101, to treat breathing abnormalities in people affected by Rett Syndrome. The drug targets a specific serotonin receptor (5-HT1A) located in regions of the brain that affect respiration, mood and cognition.  It’s possible that, beyond breathing, the drug may also improve other core symptoms such as anxiety and movement disorders.

Neurolixis has already obtained Orphan Drug status for NLX-101 in both the US and in Europe. This designation provides the company with certain financial incentives as part of the Orphan Drug Act.  

Previous RSRT funding to Neurolixis focused on studies to determine dosage levels for human studies. The next step is for Neurolixis to file an Investigational New Drug (IND) application with the FDA before clinical testing of the drug can begin.

The current award will be used to manufacture and characterize clinical supplies of NLX-101, and to prepare regulatory documents for submission to the FDA. The goal is to have the IND submitted to the FDA within a year.  Once the IND is open, Neurolixis will test the safety, tolerability and pharmacokinetics (the time course of the drug’s absorption, bioavailability, distribution, metabolism and excretion) in healthy volunteers and in people with Rett.

By supporting this program, RSRT will help Neurolixis “de-risk” the project and make it more attractive to investors, who can support the next stage of development and expedite the process. 

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