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7Year

 

by Monica Coenraads

Today is the seven-year anniversary of the launch of RSRT. In the midst of crazy schedules and workloads, anniversaries offer an opportunity for a few quiet moments of reflection on both achievements and challenges ahead.

For me the last 7 years, while demanding, have been the most rewarding of my life. To be given the freedom, the confidence and the trust by my board, our donors and the families that raise funds to pursue the work that will one day free our girls, my precious Chelsea included, is a gift that I cherish.

While science can never move fast enough to satisfy my maternally inspired timeline for a cure, I recognize that the Rett research field has come a very long way in the past 7 years. And it’s satisfying to know that RSRT has had more than a tad to do with this progress.

From the get-go RSRT was committed to funding people and projects with the potential to dramatically change the lives of our girls. Settling for marginal improvements is simply not good enough.

An exciting area of research, activating the silent MECP2 on the inactive X chromosome, was put on the research map by RSRT. It wasn’t easy as scientists were skeptical and hesitant. We started by funding one lab, then two, then another joined. Today we are supporting six labs that are trying synergistic approaches to waking up the back up MECP2 gene. These scientists have bucked the traditional “we work alone” mentality that plagues science and are showing remarkable openness and trust as they share their data, brainstorm and troubleshoot, via in-person meetings and conference calls.

Industry is showing interest in this approach due to the advantages that it brings: the approach addresses the root of the problem, you don’t have to deliver MECP2….it’s already there; no worries of having too much MECP2; the approach would be pharmacological (a drug) rather than biological (gene/protein therapy).

Another approach that has been put on the map by RSRT is the hunt for modifier genes that dampen the ill effects of an MECP2 mutation. The first modifier, squalene epoxidase, was published in 2013 by Monica Justice and has led to a clinical trial currently ongoing at Children’s Hospital at Montefiore in the Bronx.

The screen is now just over halfway through and Dr. Justice has identified several dozen modifiers. Interestingly, the modifiers are not ad hoc all over the genome but rather are falling within distinct molecular pathways. By the time the screen is done we may have 50 or so modifiers some of which will undoubtedly be druggable. Dr. Justice’s data has also revealed that Rett Syndrome has characteristics of metabolic disease, something that had not been fully appreciated before.

Rett is a complex problem and no single lab has the expertise and resources to eradicate it. So early on RSRT cultivated an environment where collaborations could flourish. While such partnerships cannot be imposed, they can be nurtured and RSRT has done just that with our MECP2 Consortium, which launched in 2011 and our Gene Therapy Consortium that started two years later. Scientists who were previously competing are now working together to solve difficult problems.

The most dramatic evidence that our science is maturing and that progress is being made is the interest in Rett from pharmaceutical and biotech companies. I’m sometimes tempted to pinch myself to make sure I’m awake and not dreaming. Scientists studying many other diseases including autism would give their right arms to be where we are at this very moment.

Along the way I’ve learned a few valuable lessons:

  1. Do not fall in love with the science that we fund. To do that means to lose objectivity.
  2. Stay nimble – new technologies and data must continually be monitored for and adopted when appropriate.
  3. Don’t become insulated – RSRT is constantly soliciting feedback on “everything Rett “– every paper that comes out and every announcement that is made receives a thorough objective and comprehensive analysis
  4. Don’t accept dogma without proof
  5. Surround yourself with smart and creative people – mediocrity won’t cut it

While it’s healthy and necessary from time to time to step back and recognize our achievements, the time to celebrate has not yet arrived. That time will come when our girls are healed and can celebrate with us.

For now there are challenges ahead and lots of work still to be done. Speaking of which…. back to the real work at hand for me.

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.

slink_closed

 

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.

 

slink_open

 

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.

 

 

Fagiolini

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.