14th Rett Syndrome Research Symposium Outcomes

July 18, 2016

Rettsyndrome.org is pleased to announce we undoubtedly had another successful research symposium to encourage communication and collaboration within the Rett researcher community.  Together, our session chairs put together a program that brought together clinical researchers, academic basic discovery and translational research faculty, pharma and biotech scientists and leaders, students and postdoc trainees, and other medical professionals.  Over 125 attended the research symposium that included 35 individual platform talks and 43 poster presentations.  We could not have asked for more.  The feeling of unity and strength was present during the meeting, and we believe all left with the feeling of hope for the future.  Hope for the treatments and therapies on the horizon for all those touched by Rett syndrome.  Thank you to our session chairs, speakers, attendees, partnerships, board of directors, and most importantly to our families, sponsors and donors.

Alan Percy, MD receives the Lifetime Achievement Award for Rett syndrome research and patient care

After Dr. Percy delivered the Keynote Talk “A Look Back at Rett Syndrome with a View to the Future”, Rettsyndrome.org Board member and Chief Operating Officer Gordon Rich presented Dr. Percy with the Lifetime Achievement award at the Thursday’s Banquet Dinner. 

 Advances in Clinical Research & Trials

Speaker Jeffrey Neul, MD, PhD speaking at Wednesday’s opening session.
“Past, Present and Future: A program to develop and establish Trofinetide as a safe and effective treatment for Rett syndrome”   

Dr. Jeffrey Neul, session co-chair of Wednesday’s session, stepped in to speak on behalf of Dr. Daniel Glaze who could not attend the symposium due to the unfortunate storms that delayed flights around Chicago.  Dr. Neul covered the past and current trial of trofinetide (glycyl-L-2-methylprolyl-L-glutamic acid, developed by Neuren Pharmaceuticals LTD), which is an analog of IGF1 [1-3] (glypromate) that shares similar biological properties with this agent. Trofinetide can be given as an oral preparation with improved systemic availability and increased plasma half-life.

Currently Neuren is conducting a clinical trial to examine safety and tolerability (primary outcome measure) in children with Rett syndrome during a multi-center, phase 2 double blinded, randomized placebo controlled clinical trial comparing 56 days of treatment with placebo or one of 3 doses (50, 100, 200 mg/kg twice a day) of Trofinetide.  Anticipated enrollment is 76 female subjects with Rett syndrome and a MECP2 mutation, and between the ages of 5 and 15 years.  Nine (9) of the planned eleven (11) sites are actively enrolling, see rettstudy.com for more details. Upon successful completion of the current study, they anticipate initiation of a phase 3, pivotal clinical study of trofinetide in Rett syndrome.   Neuren is working closely with the FDA to develop primary and secondary efficacy measures.  The results of the first 2 trials will provide informative data regarding these measures, as well as, pharmacokinetics and dosing of trofinetide.

Rettsyndrome.org has supported the first Phase 2 trial in adults with Rett syndrome through an ANGEL grant, and will fund $1M to the current and largest ever clinical trial for Rett syndrome. 

Fundamental Science and Discoveries

Speaker Michael Brenowitz, PhD speaking at Thursday’s morning session.
“MeCP2, the protein, still surprises”


Dr. Michael Brenowitz from the Albert Einstein College of Medicine in New York was invited to give a short talk at the Fundamental Science and Discoveries Session of the symposium.  Dr. Brenowitz studies the MeCP2 at the protein level.  It is a multifunctional protein that guides neuronal development through a multitude of processes that reshape chromatin and regulate gene transcription. His team began exploring the nature of MeCP2’s interaction with DNA by studying in isolation one of its six domains, MBD, whose ability to bind mCpG sites in DNA is well documented. The energetic character of MBD binding is distinctive; discrimination of modifications is conferred by suppression of binding to unmodified DNA rather than enhanced affinity for mCpG.  Equally unusual, MBD takes up monovalent cations during DNA binding suggesting that ions rather than water coordinate between DNA modifications and the protein. Study of the energetics of DNA binding by full-length MeCP2 reveals that its binding cooperativity, mediated by the C-terminal domains, enhances DNA binding affinity but suppresses discrimination of modified DNA. Modification discrimination requires cooperativity suppression that in vitro is achieved by elevated total cation concentration or by substitution of the chloride anion. In addition, protein-stabilizing solutes reduce DNA binding affinity by up to two orders of magnitude suggesting that C-terminal polypeptide flexibility is essential to high affinity DNA - binding by MeCP2. NMR analyses show that ions have discrete effects on the structure of MeCP2. They are exploring the hypothesis that the biological function of MeCP2 involves at least two discrete processes: Cooperative binding efficiently displaces linker histone from chromatin gaining access to modified DNA sites. Cooperativity is then suppressed to allow localization at sites of modified DNA. Intracellular concentrations of chloride and sodium, ions that synergistically affect DNA binding by MeCP2, change during neuronal development and could act as a molecular switch of its regulatory function.

Dr. Brenowitz is a Professor of Biochemistry and his project is supported by a Basic Research Grant from Rettsyndrome.org in 2014.

Translational Research Advances & Challenges

Session Chair and Speaker Alysson Muotri, PhD speaking at Thursday’s afternoon session.
“Modeling MECP2-related disorders with human stem cells”

Amendment 4369
Amendment 4369

Dr. Alysson Muotri from the University of California in San Diego has long been interested in modeling Rett syndrome.  Rettsyndrome.org has previously funded Dr. Muotri on projects involving induced pluripotent stem cell (iPSC)-derived neurons obtained from RTT patients. They have shown that morphological and functional defects in these neurons, and now have extended their studies to generating astrocytes (another cell type found in the brain) from iPSCs. Dr. Muotri has reported that RTT-derived astrocytes showed significant gene expression and physiological differences when compared with normal control astrocytes. By mixing RTT astrocytes with normal neurons (to simulate what happens in the brain where astrocytes and neurons reside together), they found that there was a negative impact on the development and maintenance of normal neurons. In contrast, normal astrocytes mixed with RTT neurons were able to rescue many RTT neuronal phenotypes. Dr. Muotri also reported that they identified a potential therapeutic opportunity by targeting astrocyte-release cytokines – a type of chemical messenger molecule. Dr. Muotri’s findings demonstrate the reconstitution of a complex neuronal-astrocytic system in which the contribution of specific cell types to RTT can be distinguished.

Dr. Muotri is an Associate Professor in the Departments of Pediatrics and Cellular & Molecular Medicine.  His project was supported by a Basic Research Grant from Rettsyndrome.org in 2012.

Newron Pharmaceuticals announces the Burden of Illness study

Newron Pharmaceuticals announces that it is sponsoring a study to evaluate the burden of disease experienced by patients with Rett syndrome and their families. Rettsyndrome.org’s Steve Kaminsky and Paige Nues participated in the first meeting of the Burden of Illness Working Group last week in Chicago prior to the 14th Rett Syndrome Research Symposium. We applaud Newron for taking on this important study. Quoted from Dr. Percy, this study will “help guide physicians, caregivers and policy experts about the human and financial cost of this devastating disease.”