Research Awardees: 2012

ANGEL Awards
HeART Awards
Basic Research Grant Recipients
Mentored Training Fellowship Recipients
Contracts

ANGEL Awards

Walter Kaufmann, MD, Children’s Hospital Boston
Daniel G. Glaze, MD, Baylor College of Medicine
Jeffrey Neul, MD, PhD, Baylor College of Medicine

Walter Kaufmann, MD, Children’s Hospital Boston
“A Phase 2b placebo-controlled cross-over study of rh-IGF1 (mecasermin [DNA] injection) for treatment of Rett syndrome and development of Rett-specific novel biomarkers of cortical and autonomic function”

Lay Description:
RTT is a severe genetic form of autism in girls. Girls with RTT have abnormal growth, movement problems, and abnormal patterns in breathing and heart rate. There is no treatment for RTT. Mice with the equivalent genetic change have symptoms similar to those of human patients. Treating these mice with a drug called IGF-1 relieves a large number of these symptoms. IGF-1 is already available for use in children. We propose to evaluate the safety and effectiveness of IGF-1 when given to girls with RTT through the use of non-invasive tools to measure improvements in brain activity, breathing, and heart rate during treatment with IGF-1. We anticipate that our results will set the groundwork for a larger investigation of the efficacy of using IGF-1 in children with RTT and related developmental disorders.

 

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Daniel G. Glaze, MD, Baylor College of Medicine
“A randomized, double-blind placebo controlled trial of NNZ-2566 (IGF-1{1-3}, glycyl-L-2-methylprolyl-L-glutamine acid) with open label extension in adults with Rett syndrome”

Lay Description:
Rett syndrome (RTT) is a severe disorder that causes a catastrophic loss of function in early infancy. The disorder affects many parts of the body and can produce seizures, cause curvature of the spine, and alter heart and breathing function. There is no treatment for Rett Syndrome and affected people are at greater risk of sudden death than the general population. In this project we propose to investigate a new drug called NNZ-2566 to see if it is safe and effective in the treatment of adult Rett syndrome patients. The project will involve two phases. Phase 1 will involve a 5 day open label drug treatment in which patients know they are receiving the drug. In phase 2 subjects will be assigned randomly to different groups and each group will either receive a placebo (sugar pill) or a low or high dose of the drug. In phase 2 patients and investigators will not know who is receiving drug treatment. Measures of drug safety and effectiveness will be the major focus of this study and will be collected during both study phases.

 

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Jeffrey Neul, MD, PhD, Jeffrey Neul, MD, PhD, Baylor College of Medicine
“Nonsense suppression as a therapeutic approach to Rett syndrome”

Lay Description:
Almost all patients with Rett syndrome (RTT) have mutations of the gene that makes a protein called Methyl CpG Binding Protein 2 (MeCP2). Approximately one-third of patients have "nonsense" mutations, which result in an incomplete MeCP2 protein. Recently, a number of new chemicals have been identified that allow cells to make complete proteins by 'reading through' nonsense. These include two chemicals, PTC124 and PTC7207, which were discovered by PTC Therapeutics (New Jersey). PTC124 and PTC7207 can be given by mouth and are less toxic than many other chemicals that have the same activity. PTC Therapeutics currently is testing PTC124 in patients with cystic fibrosis and Duchenne muscular dystrophy.

To study 'read through' of MeCP2 mutations, we helped IRSF develop a mouse strain that has a R255X mutation, which is like a mutation found in ~7% of patients with RTT. Other laboratories created mice that do not make any MeCP2 and they have very similar characteristics. We propose to treat male and female mice with PTC124 and PTC7207 to determine whether the symptoms are less severe and see how this correlates to the amount of MeCP2 protein that is made. We will use cells that come from these mice to optimize the read through process and will develop a test that can be used to screen for new chemicals that can read through the four most common MeCP2 nonsense mutations. Together, these studies will help determine whether this kind of treatment is potentially useful for RTT patients.

 

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HeART Awards

Daniela Brunner, Ph.D, PsychoGenics Inc.
Aleksandra Djukic, MD, PhD, Montefiore Medical Center, Albert Einstein College of Medicine
Lee-Way Jin, MD PhD, Regents of the University Of California - Davis
Kevin Foust, PhD, Ohio State University
Daniel Glaze, MD, Baylor College of Medicine
Steven Gray, PhD, University of North Carolina at Chapel Hill
Kevin Jones, PhD, University of Colorado-Boulder
Jay Shapiro, MD, Kennedy Krieger Institute
Dag Yasui, PhD, Regents of the University Of California- Davis

Daniela Brunner, Ph.D, PsychoGenics Inc.
“PPAR-sparing insulin sensitizers for Rett Syndrome”

Lay Description:
Mitochondrial function deficit and reduced BDNF levels are key precipitators of Rett syndrome. In particular, mitochondrial dysfunction may result from an imbalance in the components of the respiratory complex of the mitochondrial electron transport chain secondary to the loss of MeCP2 function (fundamental component leading to proper energy balance in living cells). Compounds that help restore the balance of mitochondrial function and BDNF function, therefore, might have a positive effect. MSDC-0160 is a PPAR-sparing insulin sensitizer that is currently undergoing clinical development for type 2 diabetes (Phase 2b) and Alzheimer’s disease (Phase 2a). This compound is a member of a new class of agents that spares PPAR activation having its primary action on mitochondrial metabolism. In mice, the pharmacology of this compound is correlated with an increased expression of mitochondrial proteins. Recent evidence demonstrated that a 3 month treatment of female 5X FAD mice, an Alzheimer’s model, with daily 30mg/kg MSDC-0160 affects several processes that might be predicted to positively impact the symptoms in RTT. We will test whether MSDC-0160 can impact the behavioral and health deterioration course of male Mecp2 RTT mouse model and also assess the compound effects on mitochondrial mass and brain BDNF levels.

 


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Aleksandra Djukic, MD, PhD, Montefiore Medical Center, Albert Einstein College of Medicine
“Language comprehension and processing in Rett syndrome: A pilot study of eye tracking”

Lay Description:
Girls with Rett Syndrome (RTT) have severe communication impairments; most communicate through vocalizing, facial expressions and eye gaze. Severely limited hand function prevents them from pointing or manipulating objects, making attempts to assess receptive language abilities through conventional tools inconclusive. Anecdotal evidence, however, indicates that girls with RTT have more language knowledge than what standardized testing, inventory and natural observation have revealed but it is not at all clear how to assess language abilities accurately. Because vision and gaze are the most important ways in which girls with RTT relate to the world, assessing their knowledge using eye tracking technology appears to be an ideal methodology. Our study of nonverbal cognitive processes in 50 consecutive girls revealed that the use of eye tracking technology is feasible and can provide quantifiable and reliable outcome measures. We propose to continue our study of cognitive functioning in girls with RTT using eye tracking technology to examine their language comprehension. Two other studies have done so with conflicting results. Our study will be based on eye tracking paradigms developed for studying language abilities of infants and young children and older children and the techniques we have developed that enabled us to successfully assess nonverbal cognitive processes. We will compare these results with assessment tools typically used with girls with RTT and correlate the findings with a descriptive analysis of the characteristics of the girls, their development and clinical features.

 


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Lee-Way Jin, MD PhD, Regents of the University Of California - Davis
“Preclinical studies of allopregnanolone, a positive GABAA receptor modulator”

Lay Description:
Major debilitating symptoms of Rett syndrome (RTT) include seizures and respiratory disorders. Recently, the loss of the inhibitory signals in the brain conducted by the neurotransmitter GABA has been shown to play a significant pathological role in RTT mouse models. Augmenting GABA neurotransmission has been shown to improve the respiratory function in a line of RTT mice and to prolong survival. A reasonable therapeutic approach, therefore, would be to induce long-term enhancement of GABA neurotransmission, which could suppress seizure activity and improve respiratory function in girls with RTT. However, all currently clinically available drugs are either with significant side effects or inducing tolerance, therefore not suitable for long-term use. In this proposal, we plan to test the therapeutic effects of a naturally occurring brain steroid called allopregnanolone. We have studied allopregnanolone for many years and know how it works in suppressing seizures and how it is distributed and metabolized in the body. Importantly, this drug has little side effects. Recently we have improved the drug properties of allopregnanolone by dissolving it in canola oil that is completely safe for human consumption orally. In addition, we have a batch of FDA-approved GMP (Good manufacturing Practice) material, ready for clinical trials. With the help of the IRSF HeART award, we will examine the effects of this oral formula of allopregnanolone on the RTT model Mecp2-/+ mice. We hope that experiments proposed in this application could enable the rapid development of a new and mechanistically novel drug for the treatment of RTT.

 

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Kevin Foust, PhD, Ohio State University
"AAV Gene Therapy for MECP2 Duplication"

Lay Description:
Currently no therapy is available to reduce the amount of MECP2 in those with MECP2 duplication syndrome. The current work proposes to develop gene therapy in animal models of too much MeCP2. A modified virus, AAV, which is programmed to reduce MECP2 levels will be used to treat an animal model of duplication syndrome. The animals will receive a one-time intravenous injection and will be studied for changes in their behavior, activity and survival. In addition, another group of animals will be treated to test for changes in the electrical signaling between the neurons in the brain. This work is important because it may prove that lowering MECP2 expression in duplication syndrome can be beneficial. 

 

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Daniel Glaze, MD, Baylor College of Medicine
"Autonomic Nervous System (ANS) Dysregulation in Rett Syndrome: Objective measures through Pupillometry and ANS Questionnaire"

Lay Description:
Rett syndrome is a disorder that alters a number of important body functions such as heart rate, breathing, the way the stomach works, body temperature and pupil size. All of these body functions are controlled by the autonomic nervous system (ANS). We propose characterization of ANS function using two non-invasive tools in 50 individuals with "classic" Rett syndrome. The first tool measures the size of the pupil using a hand-held, non-invasive recording device that is able to quickly and accurately measure pupil size in response to a fixed light. The second tool is a comprehensive ANS questionnaire designed to find problems with the ANS. With this information, we will develop and maintain a database that can serve as a reference for future clinical trials.

 

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Steven Gray, PhD, University of North Carolina at Chapel Hill
"MeCP2 gene transfer using novel RTT-specific rAAV vectors"

Lay Description:
Our lab specializes in modifying a non-disease-causing virus called AAV to deliver therapeutic genes to specific tissues in order to treat genetic disorders. We have conducted preliminary MeCP2 gene transfer studies in Rett mice with some success, but it was clear that the available AAV vectors are not ideal for eventual use in humans for treating Rett syndrome. We have engineered entirely novel AAV-based gene delivery tools, which are superior to currently available AAV vectors and specifically designed for a Rett Syndrome gene therapy approach that could be translated to humans more easily. In this application Dr. Gray will test if delivering the MeCP2 gene to Rett mice using these new AAV tools will lead a better treatment effect.

 

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Kevin Jones, PhD, University of Colorado-Boulder
"A screen for compounds that regulate BDNF expression"

Lay Description:
The production of BDNF is affected by mutation of MECP2. In animal models, increasing BDNF production or signaling through a variety of different strategies has been shown to ameliorate symptoms. These results argue that drugs that increase BDNF production could have therapeutic benefit in treating Rett syndrome. Here a series of mouse strains have been made that have different reporter genes integrated into the BDNF gene. These reporter genes encode proteins that can be easily detected. They plan to use neurons cultured from these mice to develop a more efficient method for screening compounds that can increase BDNF production. This proposal will test different culture conditions and detection methods in order to develop a screen that can be used to screen thousands of compounds. We will use such a screen to identify promising drug candidates for treatment of Rett syndrome.

 

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Jay Shapiro, MD, Kennedy Krieger Institute
"Treatment of Osteoporosis in Murine Rett Syndrome Models: A Comparison of Zoledronic Acid vs. Teriparatide on Osteoblast Function, Gene Expression and Bone Mass"

Lay Description:
This is a study of osteoporosis and its treatment in Rett. The objective is to assess the effectiveness of osteoporosis treatment with teriparatide and zoledronic acid in Mecp2 insufficiency. Preliminary data suggests that Mecp2 mutations may alter osteoblast function, therefore, the working hypothesize is that teriparatide, which stimulates osteoblastic bone formation, will be more effective in treating osteoporosis than an antiresorptive agent (zoledronic acid). Our data indicate that teriparatide improves bone mass in the male null model but has less effect in the heterozygous female. Mecp2-null osteoblast growth curves demonstrate increased cell growth and higher cell density at peak levels, a finding consistent with observations in olfactory neural cells. This study highlights the role of Mecp2 in osteoblast development and may indicate the most effective treatment options for osteoporosis in RTT. 

 

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Dag Yasui, PhD, Regents of the University Of California- Davis
"Investigation of CHRNA7 ligands as potential Rett therapies"

Lay Description:
MeCP2 expression is necessary for full expression of the neurotransmitter receptor CHRNA7 in neurons. CHRNA7 is critical in regulating the balance of neuronal circuit signaling in the brain. Impaired function of CHRNA7 function is found in a number of disorders with the loss of motor skill as seen in Rett symptoms. Drug companies have developed thousands of compounds that stimulate the activity of CHRNA7 as potential treatments for these disorders. Many of these compounds have been successfully tested in humans where they have proven to be safe and effective at reducing disease symptoms. The Yasui lab will examine the effect of CHRNA7 stimulating compounds on Rett symptoms in a mouse model. From these pilot studies they hope to advance the most promising of the CHRNA7 targeted compounds to clinical trials in RTT patients. 

 

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Basic Research Grants

Chinfei Chen, MD, PhD, Children's Hospital Boston
Yvonne Fondufe-Mittendorf, PhD, University of Kentucky-Lexington
Ali Khoshnan, PhD, California Institute of Technology
Charlotte Kilstrup-Nielsen, PhD, University of Insubria
David Lieberman, MD, PhD, University of California at San Diego
Alysson Muotri, PhD, University of California at San Diego
Michelle Olsen, PhD, University of Alabama at Birmingham
Beth Stevens, PhD, Children's Hospital Boston

Chinfei Chen, MD, PhD, Children's Hospital Boston
"Testing for Reversibility of Sensory System Circuitopathy in Mouse Models for RTT"

LAY DESCRIPTION: Recent studies in mouse models for Rett Syndrome have demonstrated that some symptoms of the disorder, such as general health conditions, defects in mobility, coordination and breathing are reversible, regardless of the age when Mecp2 expression is restored or silenced. One question that remains unanswered is whether other symptoms associated with the disorder, such as impairments in cognition, social interaction and communication can also be rescued. These features of human behavioral repertoire involve a learning process that requires children to rapidly incorporate signals from their surrounding environment during development. This experience-dependent sculpting of brain circuits usually occurs during distinct critical periods. Here we will study a sensory system that has well characterized critical periods. Our previous studies have shown that it is during these periods that neuronal circuits become abnormal in Mecp2 mouse models. Using these mouse models, we will restore or silence Mecp2 expression after the developmental critical period and test whether these sensory circuits can change even in the adult. Results from these studies will provide important information on the extent of reversibility for this devastating neurological disorder.

 

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Yvonne Fondufe-Mittendorf, PhD, University of Kentucky-Lexington
"The Epigenetic control of Gene expression by MeCP2"

Lay Description:
Proper gene regulation is important in the normal development of all organisms. When this regulation goes awry, it results in diseases such as Rett syndrome. DNA in eukaryotes found as chromatin, plays a critical role in gene regulation. Rett syndrome is caused by mutations to MeCP2, a protein than binds methylated DNA and chromatin. Despite years of studies, the functional role of this protein in gene regulation is still not fully understood. We propose to carry out studies using novel techniques that are unbiased to determine genome-wide where MeCP2 binds, what it is doing there and how does it act together with other factors to modulate gene expression. Furthermore, we will elucidate the underlying mechanisms of the structural changes on chromatin upon MeCP2 binding. These data will be critically important for the diagnosis and development of potential therapeutics critical in Rett syndrome.

 

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Ali Khoshnan, PhD, California Institute of Technology
"The role of IKK signaling pathway in Rett syndrome"

Lay Description:
Cytokines are essential for the proper development of the immune system and for its response to infection. However, abnormal cytokine levels in the brain result in neuroinflammation and disrupt the production and migration of new neurons, impair neuronal communication, and alter the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), which is reduced in Rett patient brains. Recent studies also suggest that cytokines can exacerbate the course of Rett syndrome in mice. Thus, lowering their expression may have beneficial effects. One approach is to block the cellular signaling pathways such as the IKKbeta/NF-kappa B, which control cytokine production. We plan to reduce the IKKbeta/NF-kappa B activity in the inflammatory cells of Rett mouse models and examine whether reduction of cytokines affects the development of Rett-associated symptoms. These studies could provide novel therapeutic targets for Rett. Small molecule inhibitors of IKKbeta/NF-kappa B are in clinical trials for various immune disorders, which could expedite their evaluation in Rett patients.

 

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Charlotte Kilstrup-Nielsen, PhD, University of Insubria
"Investigation of the Importance of a hitherto Uncharacterized Mecp2-Isoform for Neuronal Morphogenesis and Chromatin related functions "

Lay Description:
MeCP2 is a protein that has been found to bind and probably regulate important aspects of chromatin but it is still not clear how defects in MeCP2 cause the neurologic problems of RTT. It has become clear that MeCP2 gets phosphorylated in neurons that are activated by external stimuli but we still need to understand in more details how and when these modifications are made and what are the consequences for MeCP2 functions and the nervous system? In the past we found evidence that MeCP2 collaborates with CDKL5. In addition, we found that CDKL5 can phosphorylate MeCP2 in vitro and now we have mapped the specific target within MeCP2. Our results so far show that this particular modification of MeCP2 is mediated, at least in part, by CDKL5, that it occurs in activated neurons and that it causes the dissociation of MeCP2 from chromatin. Here we will characterize the signals causing this modification and its effects on MeCP2 functions regarding chromatin functions and neuronal development. We believe that these studies might explain how MeCP2 dysfunctions cause the RTT conditions and also provide further information of CDKL5 functions in the brain.

 

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David Lieberman, MD, PhD, University of California at San Diego
"A proteomics based approach to restore bidirectional homeostatic plasticity in MeCP2 deficient neurons in vitro and in vivo"

Lay Description:
Like a thermostat that controls temperature around a set point, neurons regulate their activity by increasing or decreasing their inherent excitability when faced with environmental changes in neuronal activity. We have found that MeCP2 deficient neurons do not respond homeostatically to changes in activity levels like MeCP2 containing neurons do. In this study, we will first compare protein levels of cultured neurons containing MeCP2 to the protein levels of cultured neurons devoid of MeCP2 under three conditions: cultures at rest, cultures that have increased excitatory drive, and cultures with decreased activity levels. Through proteomic analytic tools, we will identify those proteins whose levels are regulated by MeCP2 and are critical in allowing a neuron to properly respond to persistent changes in activity. Once we uncover which homeostatic regulator(s) are elevated with activity and decreased with inactivity, or vice versa, in wild type, but not MeCP2 knockout cultures, we will reintroduce those proteins into MeCP2 deficient neurons in culture to see if they can respond to changes in neuronal activity like MeCP2 containing neurons do. If this approach is successful in vitro, we will then reintroduce that regulator into MeCP2 deficient neurons in vivo, to see if we can rescue the structural abnormalities seen in the dendritic branches and dendritic spines of cortical neurons from MeCP2 knockout mice. These methods will uncover cellular pathways whose dysfunction is likely tied to disease pathogenesis and which then can be targeted for therapeutic intervention.

 

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Alysson Muotri, PhD, University of California at San Diego
"Contribution of Human Astrocytes to Rett Syndrome"

Lay Description:
Astrocyte function and relevance to neuron homeostasis has been proposed for more than a hundred years. At the end of the 19th century, when Cajal and Golgi made their observations regarding the types of brain cells, they made it clear to the scientific community that revealing astrocytes' role in brain development would require proper tools to identify and isolate these cells from other cell types. Up to now, most of the techniques available for studying human astrocytes are based on staining of post-mortem tissues. Thus, astrocyte specific functions are still unknown but examples of their contribution to neurological diseases strongly suggest that these cells deserve more attention. Recently, the impact of astrocytes in a mouse model for Rett syndrome suggested that these cells contribute to the disease. However, evidence that this is actually happening in Rett patients is missing. Here we propose to use astrocytes derived from human induced pluripotent stem cells to test their effects on Rett neurons carrying different types of MeCP2 mutation. Our demonstration that astrocytes can interfere with human neuronal homeostasis in RTT wills likely open new therapeutical opportunities.

 

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Michelle Olsen, PhD, University of Alabama at Birmingham
"Altered K+ ion and glutamate homeostasis in Rett Syndrome"

Lay Description:
Rett syndrome is a leading cause of cognitive, motor and communication impairment in females. In Rett syndrome patients, normal development during the first 6-18 months is followed by a period of profound regression where patients with Rett syndrome lose many cognitive and motor skills. Recent work has demonstrated that MeCP2 is expressed not just in neurons, but astrocytes. Astrocytes, which are the most numerous cell type in brain, carry out many essential functions to maintain a proper environment in the brain. Two important molecules in the brain that astrocytes are charged with regulating are potassium ions and glutamate. Too much of either can lead to abnormal brain development and seizures, a common clinical finding in Rett syndrome patients. We hypothesize that in the normal brain, the astrocytic protein that regulates potassium ions and glutamate concentration are typically regulated by Mecp2 and that in Rett patients this regulation is disrupted. Inefficient regulation of either of these molecules would contribute significantly to the abnormal brain development and seizures in Rett syndrome patients. It is our hope that by identifying a specific astrocyte proteins dysregulated in Rett syndrome, we can provide the framework for new therapeutic interventions for Rett syndrome patients.

 

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Beth Stevens, PhD, Children's Hospital Boston
"Role of Microglia at Synapses in Rett Syndrome"

Lay Description:
Interactions between the immune and nervous systems are emerging as hallmarks underlying synaptic circuit development in the CNS. Emerging evidence implicates microglia, the primary immune cell in the brain, in Rett syndrome; however the underlying mechanisms remain elusive. Our laboratory has demonstrated a surprising new role for microglia in developmental synaptic pruning in the healthy brain. We found that microglia engulf or 'eat’ developing synapses and help prune developing synaptic circuits, a process critical for precise brain wiring. Disruptions in the ability of microglia to interact and remodel synapses during this period could have significant consequences in brain wiring and synapse development. Thus it is critical that we understand how microglia are 'talking to' synapses in the developing brain and whether and how this communication is disrupted in Rett Syndrome. The proposed studies aim to investigate whether microglia-synapse interactions are disrupted in a mouse model of Rett syndrome (Mecp2 null mice) and to determine whether and how microglia dysfunction contribute to anatomical and/or behavioral abnormalities in Rett mouse models. Thus, this study would offer new insight into mechanisms of disease and possibly, the development of novel therapeutic strategies that target microglial cells.

 

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Mentored Training Fellowship

Miao He, PhD, Cold Spring Harbor Laboratory
Roberto Hirochi Herai, PhD, University of California at San Diego
Yun Li, PhD, Whitehead Institute for Biomedical Research
Annarita Patrizi, PhD, Children's Hospital Boston

Miao He, PhD, Cold Spring Harbor Laboratory
"A new mouse model for conditional MeCP2 inactivation and reactivation"

Lay Description:
MeCP2 dysfunction in GABAergic signaling is an important component of Rett pathogenesis. Deletion of MeCP2 in GABAergic neurons recapitulates most of the features displayed by Mecp2-null mice. Loss of MeCP2 in forebrain GABAergic neurons also recapitulates some features of Rett syndrome. The function of MeCP2 in GABAergic neuron development and physiology needs further investigation, especially considering the heterogeneity, prolonged postnatal maturation and plasticity of neocortical GABAergic neurons. I propose to make and use a new mouse model to evaluate the relative contribution of different neocortical GABAergic neuron subtypes to Rett syndrome pathology and investigate the function of MeCP2 during development in a cell type specific manner, which will allow me to examine the causal links from MeCP2 function to cellular, circuit, and behavior phenotypes at different stage of brain development and adult life.

 

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Roberto Hirochi Herai, PhD, University of California at San Diego
"A comprehensive analyses of transcriptomic and proteomic expression in Rett syndrome neurons"

Lay Description:
Our plan is to create a wide transcriptome profile to associate genetic alterations in Rett Syndrome with associated phenotypes. Having a Rett syndrome genetic landscape, groups researching Rett syndrome will be able to deeply analyze our findings, with the possibility to design genetic therapies to correct or ameliorate syndrome symptoms. The proposed project has the potential to dramatically change our understanding of RTT and can result in a valuable source of genetic information for potential follow-up biomarker platform development, and to better characterize how genetic alterations modulates RTT phenotypes. To better assess the biological mechanisms underlying RTT etiology, follow-up studies involves experiments beyond those ones proposed by this project to measure the phenotypic impact of gain and loss of function using cultured iPSC-derived RTT-neuron cells and mouse models. The project will be a great opportunity to improve our knowledge about RTT at the molecular and cellular levels.

 

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Yun Li, PhD, Whitehead Institute for Biomedical Research
"Modeling Rett Syndrome Using TALEN Technology in Human Pluripotent Stem Cells"

Lay Description:
To better understand the disease mechanism in Rett Syndrome and identify the most relevant therapeutic targets for patients, it is essential to gain access to human neurons with MECP2 mutation. Ideally, this human neuron-based experimental platform would be based on disease and normal cells that share identical genetic background. In the proposed study, we will use cutting-edge genomic engineering technology to create human pluripotent stem cells with MECP2 mutation. These cells will be used to make neurons and glia, and serve as an unlimited source of RTT-specific human materials. These cells will be analyzed through a panel of molecular, cellular, biochemical and electrophysiological assays. Because MECP2 mutation is the only genetic difference between control and mutant cells, it will allow us to more accurately and easily detect RTT-specific changes. The goals of our study are to identify disease phenotypes, investigate underlying mechanism, and develop potential treatment.

 

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Annarita Patrizi, PhD, Children's Hospital Boston
"Rescuing misregulation of NMDA receptor subunits in Rett syndrome"

Lay Description:
It has been proposed that the final pathway for causing Rett Syndrome is the failure of neuronal homeostasis and the disruption of the normal balance between neuronal excitation and inhibition. Restoration of adequate levels of Mecp2 in mice has been shown to reverse aspects of RTT-like symptoms. However, this approach is particularly difficult because Mecp2 gene expression is tightly regulated in the cell. We have demonstrated that in the absence of Mecp2 visual function initially develops normally but cannot be maintained into adulthood. Remarkably, selective disruption of NMDAR subunit NR2A is sufficient to restore vision, suggesting that NMDAR subunit composition may be a potential key regulator of RTT visual cortical phenotype. In the present grant, Dr. Patrizi will combine a state-of the art multi-level approach to dissect when, where and how NMDAR are disrupted in Mecp2-deficient mice and their possible regulation by drug treatment. These results will provide new therapeutic strategies for reactivating brain plasticity in RTT.

 

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Contracts

John Christodoulou, Children's Hospital at Westmead
Walter Kaufmann, Children’s Hospital Boston

Helen Leonard, Telethon Institute for Child Health Research
Jeffery Neul, MD, PhD, Jan and Dan Duncan Neurological Institute at Texas Children’s Hospital
Alan Percy, MD, University of Alabama at Birmingham
N. Carolyn Schanen, MD PhD, Nemours Research Institute/Alfred I duPont Hospital for Children

John Christodoulou, Children's Hospital at Westmead
"RettBASE Database" 

Lay Description:
The IRSF MECP2 Variation Database (RettBASE, http://mecp2.chw.edu.au) is a database comprised of published and unpublished disease causing gene mistakes (mutations) and gene changes which are believed not to be damaging (polymorphisms) pertaining to Rett syndrome and related disorders. The primary aim of RettBASE is to capture mutation data in the three genes that are currently known to cause Rett syndrome, MECP2, CDKL5 and FOXG1. 

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Walter Kaufmann, Children’s Hospital Boston
“RettSEARCH”

Lay Description:
RettSearch is an international, multi-center collaborative network of clinically-oriented researchers. Its mission is to promote the development of new therapeutic approaches for Rett syndrome by collecting information and pursuing research in areas of relevance to clinical trials in RTT. 

 

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Helen Leonard, Telethon Institute for Child Health Research
”InterRett – IRSF Phenotype Database”

Lay Description:
InterRett collects data on a worldwide basis about Rett syndrome. This international online database examines the clinical features and genetic characteristics of Rett syndrome. InterRett is playing an invaluable role in:

  • Development of partnerships between families and clinicians and in advancing knowledge about Rett syndrome
  • Increasing the clinical understanding of Rett syndrome
  • Providing a new way to help families affected by the disorder, health professionals and the general public learn about Rett syndrome
  • Encouraging collaboration with researchers from around the world

For rare disorders such as Rett syndrome, the Internet provides access to a worldwide population, providing higher statistical power than individual centers or even country based research studies. The Internet also provides an ideal medium to disseminate high quality information about a specific disorder to the medical and general community.

 

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Jeffery Neul, MD, PhD, Jan and Dan Duncan Neurological Institute at Texas Children’s Hospital
“Creation of a DNA repository for Rett Syndrome”

Lay Description:
The goal of this contract is the development of a repository of DNA collected from all participants in the Rett Syndrome Natural History project. This repository will allow the identification of genetic causes of RTT other than mutations in MECP2 and the determination of the role various genetic factors play in modifying the clinical severity in RTT.

 

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Alan Percy, MD, University of Alabama at Birmingham
“Placebo-controlled trial of Lexapro (escitalopram) for anxiety in Rett Syndrome”

Lay Description:
Mood disorders, as well as panic and fright, are frequently observed in girls diagnosed with Rett Syndrome (RTT). In addition, difficulties with motor performance, breathing and sleep disturbances may also be attributed to this high anxiety state. Thus for these reasons the specific aim of this clinical research study is to examine the efficacy of the Selective Serotonin Reuptake Inhibitor (SSRI), Lexapro (Escitalopram), in modulating maladaptive behaviors in RTT. In this pilot study, we seek to gather sufficient data that would support expansion to a full clinical trial.

 

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N. Carolyn Schanen, MD PhD, Nemours Research Institute/Alfred I duPont Hospital for Children
“Development of a Humanized Mouse Line By Knock-In”

Lay Description:
Rett syndrome (RTT) is a progressive neurologic developmental disorder and one of the most common causes of mental retardation in females. While Mecp2 point mutations in the region coding for the highly conserved MBD and disrupting the TRD domain have been shown to be associated with RTT development, the R168X and the R255X mutations are observed at frequencies of 11.8% and 4.9%, respectively. In order to generate a mouse model of this human disease, the R168X mutation will be introduced into the equivalent position with the orthologous murine gene.

 

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