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by Monica Coenraads

There is no mystery about why a girl suffers from Rett Syndrome. The cause is the mutated copy of the MECP2 gene inhabiting her cells.  But since MECP2 is on the X chromosome and all females have two X’s, beside each mutated gene rests a healthy but silenced twin. What if we could replace the flawed gene by reawakening its silenced counterpart? If we could wake up MECP2 in enough cells we could conceivably reverse Rett symptoms.

healthy-mutant

This is an approach that RSRT has championed since our launch in 2008. We are funding seven labs that are pursuing this line of work.

You may ask why do we need multiple labs working on the same goal. Isn’t that a waste of effort and money? The answer is a resounding “NO”. While the end game is the same each lab is using a different strategy to get there.

For example, the types of cells that labs are utilizing are different. Ben Philpot and colleagues at UNC are working with mouse neurons, Toni Bedalov and Jeannie Lee are using fibroblast cells, others still are using human cells. Each cell type has its own set of advantages and disadvantages.

The labs are also using different “reporters” – meaning how the cells are designed to detect activation of MECP2. Different compound libraries at different concentrations are being screened. Compounds are also being screened at various degrees of high and low throughput. And finally different criteria are being employed to define a “hit” (drugs that reactivate MECP2).

Bryan Roth

Bryan Roth gives us a tour of his robotic high-throughput
screening facility at UNC Chapel Hill

Having multiple labs attack this problem gives us more shots on goal and added assurances regarding the quality of any potential hits.

Two weeks ago we gathered everyone tackling this approach and brought them together for two intense days of talks and discussions.

Targeting MECP2 as a Treatment Strategy for Rett Syndrome
Chapel Hill, NC
May 12-13, 2014

Seventeen scientists from eight labs plus advisors from NIH and industry at RSRT meeting.

Seventeen scientists from eight labs
plus advisors from NIH and industry participate at meeting in Chapel Hill, NC.

 

Over the past 15 years I’ve organized dozens of meetings and before each one I worry – will the discussions be forced or will they flow naturally? will collaborations ensue? It was no different with this meeting.  The first few talks of the day however quickly put me at ease.  While a number of common hits were reported in multiple labs much validating and further screening remains to be done.  At the meeting, and in emails and phone calls since, the scientists are working out the logistics of validating each others hits, trading cell lines and compounds.  Exactly the outcome I was hoping for.

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by Diana Gitig

Clinical trials are designed to make sure that new therapeutics are both safe and effective. They can also be used to identify side effects, to compare how well different drugs work relative to each other and to see if certain populations react differently to different treatments. In order for doctors to prescribe the most appropriate drugs to their patients, they need to know the results of such clinical trials. Unfortunately, that information is not always so easy to come by.

Publication bias means that negative results generally do not get published. This is problematic because it skews the publication record. If only positive results get published, showing that a given drug is effective in assuaging a certain condition, people assume that that is the full story. Even if ten studies have been done showing that that same drug is useless, since negative data does not usually see the light of day no one knows about them and people think the published positive results are “fact.” Approximately half of all clinical trials performed globally have never been published in academic journals, and trials with positive results are twice as likely to be published as those with negative results. No one wants to publicize that their drug doesn’t work. Because if doctors don’t know that a drug doesn’t work – or a more realistic scenario, that a new, expensive drug doesn’t work better than the old generic – then why on earth wouldn’t they prescribe that drug to their patients? Moreover, it has been perfectly legal for pharmaceutical companies and universities to withhold the results of clinical trials as proprietary information.

To mitigate the misperceptions caused by publication bias and the withholding of trial data by the pharma industry, the Food and Drug Administration Modernization Act of 1997 created ClinicalTrials.gov. All clinical trials with at least one testing site in the US are supposed to register there before the trial starts. It went online in 2000 but only really became a force in 2005, when the International Committee of Medical Journal Editors made registration a prerequisite to having a trial published in a journal. Since researchers must register before the trial begins, they must lay out their initial hypothesis and thus cannot “move their goalposts” – claim to have always been looking for whatever it was they found. In 2007, the FDA added the requirement that results must be published on the site within a year after a trial is completed. Thus even if results are not published in journals doctors and patients have another place to search for them, and it should, in theory, be more difficult for researchers to hide negative results, since there is a record of the trial having taken place.  However, neither the requirement to register trials nor the requirement to report results have been rigorously enforced or followed. So often not only do doctors still not know the results of trials – they might not even know that a trial has been done.

On April 2, 2014, the Members of the European Parliament voted to adopt the Clinical Trials Regulation. This regulation makes it law in the European Union that clinical trials be registered before they begin, that results be published somewhere within a year after the trial ends, and that a summary of results written in lay terms be published on the publicly accessible register. Failure to comply with these new requirements will be punishable by a fine. It also dictates that information contained in Clinical Study Reports will no longer be considered commercially confidential. These reports contain many details that are often omitted in academic papers but are nonetheless important, like research methodologies.

This new European law is expected to come into effect in mid-2016 at the earliest. It is an enormous stride forward, but most of the medicines currently in use went through trials that have already been done. Results of these trials can still legally be withheld, so doctors must still make prescribing decisions without complete, accurate, and up-to-date information about which drugs now available are best for which patients.

Those with rare diseases can be particularly impacted by the transparency, or lack of it, in clinical trials. Pooling results from different studies into meta-analyses can often reveal the most telling effects of a drug; since fewer people have these disorders fewer studies can be done, and thus withholding data from any one of them can thus have an outsize effect. Moreover, subjects who participate in such trials often do so to benefit their fellow patients in addition to themselves, and withholding the results that they helped provide is a betrayal of their trust.

http://www.alltrials.net/

http://www.badscience.net/

http://www.thepharmaletter.com/article/meps-vote-for-more-transparent-and-simpler-european-clinical-trial-rules

http://www.bmj.com/content/348/bmj.g213?ijkey=5aXoYcMGOETixKf&keytype=ref

http://www.nimh.nih.gov/funding/opportunities-announcements/clinical-trials-foas/changing-nimh-clinical-trials-efficiency-transparency-and-reporting.shtml

http://www.nimh.nih.gov/about/director/2014/a-new-approach-to-clinical-trials.shtml

 

Last year RSRT awarded a $750,000 grant to Michael Green,  PhD of University of Massachusetts to pursue an unconventional approach to reversing Rett: reactivating the silent X chromosome.  UMASS just released the piece and video below highlighting Dr. Green’s work.  We are struck by the following quote from Dr. Green:  “With NIH funding, you pretty much have to be doing mainstream research. The NIH doesn’t fund bold and innovative projects often. By contrast, organizations like RSRT are willing to take on high-risk projects that have controversial hypotheses and rationales, because these are the ones that really may have a great impact on disease.”

We thank all of our supporters who make it possible for us to fund innovative, out-of-the-box projects that we believe will move us towards a cure for Rett by leaps rather than small incremental steps.

From the UMASS Med NOW website:

UMMS scientist aiding a mother’s quest for rare disease cure
With a $750,000 grant from the Rett Syndrome Research Trust, Michael Green is working to reverse a debilitating neurological disease

By Lisa M. Larson and Bryan Goodchild (UMass Medical School Communications)

Monica Coenraads is discussing work with two business associates in the living room of her Trumbull, Conn., home on a recent spring morning, when the conversation turns to the benefits of face-to-face communication over reliance on electronic devices.

Suddenly, a squeal of laughter erupts from the other side of the room, where her 17-year-old daughter, Chelsea, has been relaxing on the couch, quietly listening to her mother’s every word.

“Chelsea thinks it’s funny, because she believes her mom spends too much time on her phone,” explains Coenraads, who works from her house.

In homes across America, parents and kids are debating texting, cell phones and screen time.

But for the Coenraads family—Monica, husband Pieter, and sons Alex, 15, and Tyler, 14,—the focus is on discovering any method by which Chelsea can communicate. The slender, brilliant-blue-eyed girl, who bears a striking resemblance to her mother, has Rett syndrome, a rare, genetic, neurological disease that locks her thoughts inside her head, as she is unable to speak or to use her hands. With great determination and without speech or hand gestures, Chelsea expresses herself by focusing her gaze on pictures in a three-ring binder of the words she’d like to say.

“A child with classic Rett syndrome is in a wheelchair, unable to talk, fed through a feeding tube, with seizures, anxiety, orthopedic issues, scoliosis, contractures and no hand function,” said Coenraads, co-founder and executive director of Rett Syndrome Research Trust (RSRT) and its director of research. The former restaurateur is credited with helping to raise more than $37 million for research into Rett syndrome since her daughter’s diagnosis 15 years ago.

“They’re really trapped,” continued Coenraads, explaining the disease, which affects approximately 16,000 girls across the country. “They can understand what is going on; cognitively they are quite on track.”

UMass Medical School scientist Michael R. Green, MD, PhD, globally known for his work in gene regulation, keeps the image of Chelsea and that of other girls who suffer from Rett in mind as he works toward finding a drug that would reverse the disease. Dr. Green, a Howard Hughes Medical Institute Investigator, the Lambi and Sarah Adams Chair in Genetic Research and professor of molecular medicine and biochemistry & molecular pharmacology, received a $750,000 grant from RSRT for research aimed at reversing the underlying cause of the disorder. He is one of several dozen researchers around the world, recruited by Coenraads, who have met children with Rett and their parents, and are working on therapies, a cure or a reversal of the disease.

Rett syndrome is caused by a mutation of the gene on the X chromosome called MECP2 that causes numerous devastating symptoms that worsen over time. The symptoms begin in early childhood and leave Rett sufferers completely dependent on 24-hour-a-day care for the rest of their lives. While the function of MECP2 remains elusive, scientists know that it acts globally and impacts numerous systems in the body.

Female cells have two X chromosomes and therefore two copies of the MECP2 gene, and mutations occur in only one of the two copies of the gene. In females, however, one of the two X chromosomes is randomly turned off (or silenced), a phenomenon called X chromosome inactivation (XCI). As a result, in patients with Rett syndrome, half of the cells express a normal copy of MECP2 and the other half express the mutant copy. Importantly, in those cells that express the mutant MECP2, the normal copy is still present—just silent. Green is testing drugs that modulate XCI to reactivate the silent normal MECP2 gene in these cells as a strategy to reverse the disease.

“He is taking a somewhat unconventional approach, as he is attempting to reactivate the entire X chromosome and not just MECP2,” saidCoenraads. “His work first came to RSRT’s attention in 2009. We learned that he was conducting a screen to identify genes that control 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 Rett syndrome mouse models.”

Green praised the support he has received from RSRT and said the work that Coenraads and her colleagues do is inspirational.

“With NIH funding, you pretty much have to be doing mainstream research,” said Green, who was recently elected to the National Academy of Sciences. “The NIH doesn’t fund bold and innovative projects often. By contrast, organizations like RSRT are willing to take on high-risk projects that have controversial hypotheses and rationales, because these are the ones that really may have a great impact on disease.”

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