Previously Funded Research

Previous Years' Research Awards:

2018 Research Awardees & Funded Projects

Colleen Niswender, PhD – Vanderbilt University: Awarded: $150,000

Tailoring gene replacement therapy for MECP2-related disorders

Jeannie Lee, MD, PhD – Massachusetts General Hospital: Awarded: $150,000

Reactivating the silent MECP2 allele through a synergistic drug mechanism

Translational Research Program

Nicholas Katsanis, PhD – Duke University: Awarded: $150,000

Towards identifying therapeutic targets of MECP2 deficiency

Steven G. Kaminsky Scout Program Awards

Neuro-Habilitation Program

Mentored Training Fellowship Program

Billy Lau, PhD – University of Tennessee – Knoxville: Awarded:$100,000

Cortical inhibitory mechanism governing auditory perception in MeCP2+/-

Cary Fu, MD – Vanderbilt University: Awarded: $125,000

Characterizing Biomarkers of Epileptogenesis in Rett Syndrome


2017 Research Awardees & Funded Projects

Basic Research Program

Kevin Jones, PhD, University of Colorado, Boulder:  Awarded:  $150,000

Testing potential regulators of BDNF expression to identify candidate Rett syndrome therapeutics

Colleen Niswender, PhD, Vanderbilt University:  Awarded:  $150,000

Exploration of metabotropic glutamate receptor 3 as a target for MeCP2-related disorders

Translational Research Program

Qiang Chang, PhD, University of Wisconsin -Madison:  Awarded:  $150,000

In Vitro and In Vivo Validation of Candidate Drugs to Treat Rett Syndrome

Jeannie Lee, MD, PhD, Massachusetts General Hospital:  Awarded:  $149,996

Reactivating the silent MECP2 allele through a synergistic drug mechanism

Neuro-Habilitation Program

Pam Diener, PhD  Georgetown University:  Awarded $75,000

Virtual Reality Gaming May Support the Development of Purposeful Upper Extremity Use in Individuals with Rett Syndrome

Mentored Training Fellowship Program

Billy Lau, PhD, University of Tennessee-Knoxville:  Awarded $100,000

Co-Mentors: Stephen Shea, PhD and Keerthi Krishnan, PhD

Cortical inhibitory mechanism governing auditory perception in MeCP2+/-

2016 Research Awardees & Funded Projects

Angel Awards – Clinical Trials

Mustafa Sahin, MD, Boston Children’s Hospital

“A Phase 2b placebo-controlled crossover study of rhIGF1 (mecasermin [DNA]  injection) for treatment of Rett syndrome and development of Rett-specific novel biomarkers of cortical and autonomic function.”

Budget: $212,876


Daniel Klamer, PhD, Anavex Life Sciences

Randomized, Double-Blind, Placebo-Controlled, Dose-Titration of ANAVEX 2-73 in Patients with Rett Syndrome

Budget: $ 597,886


Contract – Clinical Trials

Neuren Pharmaceuticals

Trofinetide Phase 2 Pediatric Trial

Budget: $ 750,000

Database Grants

John Christodoulou, AM, Children’s Hospital at Westmead

RettBASE: IRSF MECP2 Variation Database – a Global Resource

Budget: $91,858

Helen Leonard, MBChB, MPH

The InterRett database: achieving international breadth and
longitudinal depth in Rett syndrome

Budget: $100,000


The Scout Program

Taleen Hanania, PhD, Psychogenics Inc.

“Drug Discovery Screen in a Mouse Model of Rett Syndrome”

Budget: $300,000

2015 Research Awardees & Funded Projects

Angel Awards – Read-Through Program

Jeffrey Neul, MD, PhD, University of California San Diego

Jeffrey Neul, MD, PhD, University of California San Diego
“UCSD Integrated Read-through Program for Rett Syndrome”

Budget: $600,000

Lay Description:
Rett syndrome (RTT) is a neurodevelopmental disease caused by mutations in Methyl-GpG-binding Protein 2 (MECP2). A significant number of people with RTT have a specific type of mutation (nonsense mutation) that acts like a “stop sign” to prevent the production of full-length protein. Recently, drugs have been developed to allow the cellular machinery needed to produce proteins to ignore these “stop signs” and make full-length proteins. Promisingly, some of this class of drugs has shown benefit in other genetic diseases such as Cystic Fibrosis and Duchene Muscular Dystrophy. Unfortunately, at this time it is unknown whether any of the existing drugs of this class will work in RTT. To address this, we designed a systematic platform to evaluate existing drugs and screen for new compounds that will work in RTT, and to test them formally in both cellular and animal models of RTT. We will make use of human patient derived cell lines to do the screening and cellular characterization. In order to be able to determine whether these drugs will work for many different MECP2 mutations, we will develop and characterize a new mouse model of RTT and use this and existing models to see if the drugs that work in cellular models will work in animals. Ultimately, we hope this platform will identify effective drugs that can be testing in people with RTT.

We will use this pipeline to evaluate a series of compounds from both PTC Therapeutics and Eloxx Pharmaceuticals to determine if any of these existing compounds are effective and can be moved into clinical trials. Once established, the pipeline can be used to screen for other read-through compounds.

HeART Awards – Neuro-Habilitation Program

Jenny Downs, PhD, Telethon Kids Institute
Susan Rose, PhD, Albert Einstein College of Medicine

Jenny Downs, PhD, Telethon Kids Institute
“An evaluation of environmental enrichment for young girls with Rett syndrome”

Budget: $144,233

Lay Description:
Girls with Rett syndrome have difficulties performing motor skills such as walking and getting up from sitting to standing. Animal studies have found that the mice with a MECP2 mutation develop better motor skills if their environment is enriched, possibly due to the extra physical activity which then increases production of Brain Derived Neurotrophic Factor (BDNF). BDNF is an important protein for nerve cell growth and maturity. For Rett syndrome, therapies should be more effective if implemented intensively at an early age due not only to inherent brain plasticity and capacity to learn but also potentially due to stimulation of BDNF production. We know that girls with Rett syndrome can learn new skills with training and practice. However, available research studies have involved small numbers of girls with no comparison group or period. We still do not know the precise benefits of intensive early intervention in Rett syndrome. This study involves collaboration between researchers and clinicians in Australia and China. Our study will recruit approximately 12 girls younger than 6 years and assess the girls during a period with no intervention and then during a nine month period with environmental enrichment. We will assess motor function, sleep, constipation, growth and serum levels of BDNF. Our study will determine the evidence base for intensive environmental enrichment for young girls newly diagnosed with Rett syndrome giving clearer guidance for both clinicians and families.

Heart – Neuro Awardees List

Susan Rose, PhD, Albert Einstein College of Medicine
“Identification of Impairments in Attention Associated with Rett Syndrome”

Budget: $149,912

Lay Description:
Attempts to assess cognitive functioning in patients with Rett syndrome (RTT) have been extremely difficult. Drs. Rose and Djukic have begun to overcome this problem in pioneering work that uses eye tracking technology, which allows them to carefully monitor how patients visually inspect faces and scenes. They have already established the feasibility of using this technology with the RTT population and found that girls with RTT are able to recognize patterns, faces, and some emotional expressions, although not as well as their typically developing peers. They also found evidence suggesting that the source of their recognition difficulties may lie in impaired attention. The scanning patterns of the RTT girls were often atypical — characterized by fewer and longer fixations, poorly distributed looking, and less looking to key target areas. They propose to continue our study of cognitive functioning in girls with RTT by examining three key aspects of attention that might be involved.  They plan to recruit 30 patients with genetically confirmed RTT and a comparison group of typically developing females matched in age. Each child will be tested on 3 tasks:  Sustained attention (which requires maintaining focus on a target while ignoring distracters); Selective Attention (finding a target in an array of distracters) and Disengagement of Attention (shifting attention from one location to another while ignoring competing information). Given that these components of attention are critically involved in memory and learning, identifying the nature of attention impairments in girls with RTT would constitute a major step forward in understanding this disorder.

HeART Awards

Seth Hays, PhD, University of Texas at Dallas
Michael Kilgard, PhD, University of Texas at Dallas
Kathleen Motil, MD, PhD, Baylor College of Medicine
Leopfold Curfs, PhD, Maastricht University

Seth Hays, PhD, University of Texas at Dallas
“Evaluation of a Novel Therapeutic Intervention to Improve Motor Function in Rett Syndrome”

Budget: $145,105

Lay Description:

Many Rett syndrome patients struggle with motor dysfunction. Rehabilitation can partially treat motor impairments in RTT patients, but intensive training is required and the results are modest. In general, rehabilitative therapy improves motor function by promoting beneficial changes in brain networks responsible for motor control. Our research group has recently developed a targeted plasticity therapy that uses vagus nerve stimulation (VNS) paired with rehabilitative training to enhance rewiring of damaged and diseased brain circuits to boost the benefits of rehabilitation. VNS paired with rehabilitation significantly improves motor function in animal models and human patients with motor deficits. VNS is safe, FDA-approved, and currently used in 60,000 patients, highlighting the therapy’s clinical viability and substantially reducing bench-to-bedside translational barriers for RTT. Based on this promising preclinical and clinical evidence, this study will provide a proof-of-concept evaluation of VNS paired with rehabilitative training to improve skilled forelimb motor function in a rat model of RTT. In addition, we will examine how VNS therapy drives beneficial changes in networks of neurons important for controlling movement. Developing an effective treatment for RTT will likely require a multifaceted approach, and the current proposal only addresses a small portion of the constellation of symptoms that accompany the disease. However, this study represents a tractable first step in developing a targeted plasticity therapy that has the potential to treat motor dysfunction and could provide significant, meaningful improvements in the lives of RTT patients and their families.

Michael Kilgard, PhD, University of Texas at Dallas
“Reversing speech sound processing deficits in Rett syndrome”

Budget: $150,000

Lay Description:

Individuals with Rett syndrome have significant impairments in their ability to understand language. Abnormal neural processing of sounds appears to play a critical role in the communication difficulties observed in individuals with Rett syndrome. Neurophysiology studies have confirmed cortical deficits in auditory processing in children and adults with Rett syndrome. Both speech discrimination ability and auditory cortical responses are also impaired in rats with a mutated Mecp2 gene. Recent studies in both humans and rodent models suggest that IGF-1 therapy could improve many of the symptoms observed in Rett syndrome. The objective of this proposal is to determine whether IGF-1 therapy can improve speech processing in the rat model of Rett syndrome. The first aim is to determine whether IGF-1 can normalize cortical responses to speech sounds in Mecp2 rats. We predict that IGF-1 therapy will be sufficient to improve the auditory cortex response to speech sounds in Mecp2 rats. The second aim is to determine whether IGF-1 can improve speech discrimination performance in Mecp2 rats. We will test two significant real world problems in Rett syndrome, identifying speech in a noisy background and identifying speech from a rapidly presented continuous stream of speech sounds. We will evaluate the ability of IGF-1 to reverse speech processing problems in Mecp2 rats. Insights derived from this work could lead to the development of novel therapies to refine the neural responses to speech sounds and thereby enhance speech and language function, significantly improving the lives of individuals with Rett syndrome.

Kathleen Motil, MD, PhD, Baylor College of Medicine
“Characterization of the Gut Microbiome and Metabolome in Rett Syndrome”

Budget: $149,995

Lay Description:

Gastrointestinal problems are common in girls and women with Rett syndrome (RTT) and pose a substantial medical burden for their caregivers. Treatments for gastrointestinal problems in RTT are limited. Recent animal studies suggest that changes in the bacteria (microbiota) of the gastrointestinal tract may affect the function of the nervous system of the brain and/or gut.  Because girls and women with RTT have gastrointestinal problems, we suspect that alterations in the gut microbiota may underlie intestinal dysfunction in these individuals. To better understand the problem, we plan to characterize the composition of gut bacteria and measure their metabolic end-products in 25 girls with RTT and 25 unaffected siblings or relatives. We will obtain stool samples from both groups of girls and perform a genetic analysis of gut bacteria composition and a biochemical analysis of their metabolic end-products in fecal specimens. We will collect additional information about each girl’s clinical severity of RTT, her gastrointestinal symptoms, quality of life, body composition, dietary intake, and medication use, and relate these factors to differences in gut bacteria composition and metabolic end-products between both groups of girls. The goal of the project is to develop strategies for new and improved treatments for gastrointestinal symptoms in RTT, based on a better understanding of the gut microbiota of affected individuals. This project will potentially lead to improved health and quality of life for girls and women affected by RTT.

Leopfold Curfs, PhD, Maastricht University
“Development of Clinical Guidelines for the Management of Communication in Individuals with Rett Syndrome”

Budget: $122,240

Lay Description:

The number of specialist multidisciplinary centres for the care and management of individuals with Rett syndrome (RTT) is growing internationally and the number of clinicians with specialist skills who work in independent practice or local teams is also gradually expanding. However, there is huge variability in knowledge and expertise between countries, huge variability in clinical practices both between and within countries, and parents report their struggle to access appropriate, knowledgeable, timely and ongoing assessment, intervention, technology, support and advice tailored to the specific communication needs of their families.  There is a pressing need to develop internationally-agreed guidelines which can be followed by specialist centres and by clinicians in the local community to facilitate and optimise the communication skills of individuals with RTT and which ensure consistent information regarding the management of communication is provided to families across the globe. This project will create clinical guidelines relating to the assessment, intervention and longer-term management of communication in individuals with RTT. The guidelines will empower families and professionals, giving them an opportunity to work together in the design of best-practice intervention programmes to enhance the communication of individuals with RTT.

Basic Research Awards

James Eubanks, PhD, University Health Network
John Lukens, PhD, University of Virginia
Sampathkumar Rangasamy, PhD, Translational Genomics Research Institute
Mojgan Rastegar, PhD, University of Manitoba

James Eubanks, PhD, University Health Network
“Investigating TRPM2 As A Therapeutic Target For Rett Syndrome”

Budget: $100,000

Lay Description:

Recent advances in our basic science understanding of how a MeCP2 deficiency affects brain function has identified new systems that likely contribute directly to Rett syndrome pathophysiology. Using these new findings as guides, we looked for new targets whose altered functions would be predicted in the MeCP2-deficient brain based on these new results. One exciting new potential target that emerged was a member of a family of factors whose activity is already known to negatively affect brain function when over-active.  We tested whether this factor, designated TRPM2, might play a role in Rett syndrome by genetically removing it from MeCP2-deficient mice.  The results were remarkable — the Rett syndrome mice lacking TRPM2 lived twice as long, had significantly improved behaviors, and displayed fewer epileptic discharges than untreated MeCP2-deficient mice.  Based on these outcomes, we propose that TRPM2 does contribute to Rett syndrome, and that it might be targetable for therapeutic development.  This project will investigate potential mechanisms through which deleterious TRPM2 activity could arise in the MeCP2-deficient brain, and test whether specific drugs that block TRPM2 will improve the function of MeCP2-deficient neurons.  If successful, the results from this study will lay the groundwork to further develop TRPM2 drugs for their potential use in treating Rett syndrome.

Basic Awardees List

John Lukens, PhD, University of Virginia
“Targeting IL-1-mediated inflammation and associated dysbiosis to treat Rett syndrome”

Budget: $100,000

Lay Description:  

Mounting evidence has linked dysregulated immune response and changes in microbiota (commensal bacteria that reside in humans) to the development of several neurodevelopmental disorders. For instance, inflammatory molecules that are generated by immune cells have been shown to cause behavioral abnormalities and neurodevelopmental impairments. Furthermore, emerging data suggest that inflammation- induced changes to the microbiome can provoke the development of autistic-like behaviors. Recent clinical and epidemiological studies also demonstrate that abnormalities in CNS development are often associated with dysregulated immune responses, gastrointestinal inflammation, and dysbiosis (imbalance in microbiota that correlates with disease). Despite these major advancements in our understanding of neurodevelopmental disorder etiology, the contributions of aberrant immune responses and associated dysbiosis in Rett syndrome has not been formally investigated. In preliminary studies, we found that Rett syndrome disease progression is associated with enhanced levels of the inflammatory cytokine interleukin-1 (IL-1) and marked changes in the microbiome. Moreover in our studies, reconstitution of a healthy microbiome by fecal transplantation limited the development of Rett syndrome. These findings identify previously unrecognized roles for the microbiome in Rett syndrome and define MECP2 as a novel negative regulator of IL-1 production. The completion of the studies proposed in this grant will provide novel insights into the roles that dysregulated immune responses and inflammation-induced dysbiosis play in Rett syndrome. IL-1 neutralizing therapeutics and probiotics have shown great promise in the treatment of other pediatric disorders, thus similar approaches may offer a desperately needed treatment option for Rett syndrome.

Sampathkumar Rangasamy, PhD, Translational Genomics Research Institute
“Role of mTOR pathway in the pathogenesis of Rett syndrome”

Budget: $99,318

Lay Description:

Rett syndrome, which is caused by mutation of the MeCP2 gene, is an important example of an ASD with a known genetic cause.  The goals of our research are to understand the molecular mechanisms by which MeCP2 mutation leads to neuronal abnormalities (small size, stunted branching) and develop new therapeutic approaches for this group of conditions.   We have made an important and novel observation — that in at least one Mecp2 mutant mouse model, a key component of the mTOR cellular growth pathway is down-regulated.  mTOR is a critical protein found in all cells, and is a central regulator of cell growth.  mTOR has received a lot of attention because it is important for other neurodevelopmental disorders (such as tuberous sclerosis complex) and in cancer biology. We will use biochemistry, molecular biology, next generation sequencing and bioinformatics tools to characterize in detail the link between MeCP2 and the mTOR pathway in several MeCP2 mutant mouse models.  We will then test if manipulation of mTOR both in Mecp2-mutant animals (by genetic manipulation) and in cultured neurons, rescues the pathological features seen in the brain.  We expect that the outcomes of our research will help in development novel therapies targeted towards specific molecular pathway in treating Rett syndrome.

Mojgan Rastegar, PhD, University of Manitoba
“Investigating the Molecular Mechanisms of MeCP2 Isoform-Specific Regulation in Brain Cells”

Budget: $100,000

Lay Description:

MeCP2 mutations lead to Rett Syndrome, a progressive neurodevelopmental disorder in young females that currently has no cure. Rett Syndrome patients seem to born and develop normally at birth, but by 6-18 months of age they start to display disease-associated phenotypes that include loss of speech, reduced motor control, epilepsy, anxiety, mental retardation, and autistic behaviors. MeCP2 is an important protein for normal brain development and function with a tightly regulated expression levels in the brain. Two MeCP2 protein variants (isoforms) exist that are called E1 and E2, with E1 being the relevant protein variant for Rett Syndrome. Studies in MeCP2-deficienct mice indicate that both E1 and E2 can rescue the disease-associated phenotypes with different efficiencies. We have studied the functional role of MeCP2 protein variants, as well as their expression and regulation during brain development and in different parts of the brain. In our lab, we use reproducible systems in mice and human brain to determine how molecular deficiencies at the cellular levels lead to impaired brain function in Rett Syndrome. In this application, we propose to investigate the molecular mechanisms that regulate MeCP2 isoforms in different brain cell types and to elucidate the impact in Rett Syndrome patient samples. The outcome will be important for designing future therapeutic strategies for Rett Syndrome, especially in cases that only one isoform is affected and one healthy protein variant still exists in the brain cells.

Mentored Training Fellowships

Marisela Dy, MD, Boston Children’s Hospital
Keji Li, PhD, Massachusetts Institute of Technology
Timothy Hammond, PhD, Boston Children’s Hospital, Harvard
Pinar Mesci, PhD, University of California San Diego

Marisela Dy, MD, Boston Children’s Hospital
“Characterizing and evaluating movement disorders and understanding structural and functional network abnormalities in Rett Syndrome”

Budget: $250,000

Lay Description:
Rett syndrome (RTT) is a neurodevelopmental disorder known to have movement abnormalities. One of the main diagnostic criteria is hand stereotypies. RTT patients are also known to have hyperkinetic (unwanted or excess) and/or hypokinetic (reduced or decreased) movements. Currently, there is no quantifiable measurement of stereotypic (e.g., hand stereotypies) and non-stereotypic movements (e.g., tremor, dystonia, chorea, myoclonus). There is also a paucity of research in non-stereotypic movement disorders in RTT. We will create a video scoring tool to identify other features associated with hand stereotypies as well as the presence of other movement abnormalities. Actigraphy will be analyzed by biomedical engineer to determine if there are specific signals (e.g., position, translation, rotation, and the frequency of peak spectral power in the x, y, and z directions) associated with patterns observed in videotaped analyses. In addition, we will use standardized movement disorder scales to better characterize other movement disorders in RTT. We hypothesize that a more careful assessment of movement disorders found in RTT is essential to determine optimal drug therapy and improve motor function. To understand the connection between other movement disorders that occur in RTT with underlying pathophysiology, we will use multi-modal imaging techniques and correlate with movement disorder and clinical severity. The overall goals are to understand the pathophysiology of movement abnormalities in RTT and create objective measures that can be used in future clinical trials or drug treatments of patients with RTT.

Keji Li, PhD, Massachusetts Institute of Technology
“Synaptic mechanisms and novel therapeutic strategies for Rett Syndrome”

Budget: $100,000

Lay Description:
How Rett Syndrome (RTT) disrupts brain function is not well understood. Neurons connect with each other to form neuronal networks which carry out computations that enable behavior and cognition. Two main types of neurons include excitatory neurons, which make their target neurons more likely to be active, and inhibitory neurons, which work the opposite way. Neuronal activity is determined by the number, strength, and timing of the inputs that a neuron receives. The excitatory (E) and inhibitory (I) inputs onto pyramidal neurons, which are the main long-range projection neurons of the brain, are delicately balanced. The normal spatial/temporal pattern of this E/I balance is essential for many brain functions. E/I balance is altered in RTT, disrupting cognitive functions. Using sophisticated techniques in model mice, I will measure how E/I balance is altered in RTT. I hypothesize that both excitatory and inhibitory inputs are reduced in RTT, with inhibitory inputs reduced to a greater extent. I further hypothesize that the inhibitory inputs are so greatly reduced because a biophysical property of neurons that regulates inhibition is disrupted. I will measure these biophysical substrates in detail. Finally, I will test a new treatment of RTT using a combination of two drugs: one that enhances excitatory drive, and another that enhances inhibitory drive. My hypotheses suggest that a combination of these drugs can better correct the dysfunction found in RTT than either drug alone. If successful, this research will pave the way for clinical tests of a new treatment in human RTT patients.

Timothy Hammond, PhD, Boston Children’s Hospital, Harvard
“Understanding microglia diversity and IGF signaling in Rett Syndrome”

Budget: $100,000

Lay Description:
Ongoing clinical trials for the recombinant IGF-1 (Mecasermin) and IGF-1 analogue NNZ-2566 (Trofinetide) have raised the exciting possibility that a treatment for Rett syndrome is near, but our understanding of how these drugs produce beneficial effects in Rett individuals is unclear. Previous studies have shown that Mecp2 null mice have lower than normal levels of IGF-1 in the brain but the consequences of this reduction and the specific mechanisms that regulate IGF-1 signaling in the Rett syndrome have not been explored. Interestingly, our lab has found that microglia — the immune cells of the brain — are a major source of IGF-1 in the human brain and also express receptors for the hormone. Microglia are important for the normal function of brain networks so understanding how they respond to IGF-1 and whether reduced IGF-1 levels alter their function is essential. We will use a combination of Rett mouse mutants and microglia cell cultures to examine how Mecasermin affects critical microglia functions like providing support to neurons and the pruning neuronal synapses. We will also use a new sequencing technique to see whether certain microglia in specific brain regions are most affected in Mecp2 null mice. Overall, our results will help provide key insights into how the current IGF-1 therapies for Rett syndrome work, and uncover ways to improve them in the future.

Pinar Mesci, PhD, University of California San Diego
“Exosome-mediated cell-cell communication in Rett Syndrome”

Budget: $100,000

Lay Description:
Development and maintenance of neuronal circuits requires a complex series of events involving coordinated communication between multiple cell types over multiple length scales of space and time. The known mechanisms underlying the cell-cell communication include gap junctions, cell adhesion, and release of bioactive molecules such as neurotransmitters and growth factors. The possibility that exosomes, a type of extracellular membrane vesicles, function as a novel type of cell-cell communication to establish and maintain neuronal circuits have not been explored. We propose to test the hypothesis that exosomes provide cell-cell communication required for the development and continued function of neural circuits, and that exosome-mediated signaling is deficient in Rett syndrome (RTT). Our aim is to establish a novel role for exosomes in the nervous system, identify genes that regulate exosome pathway and could therefore be potential drug targets, and discover companion diagnostic biomarkers for neurological diseases, such as Rett syndrome.

Clinical Trial Funding

Mustafa Sahin, MD and Walter Kaufmann, MD, Boston Children’s Hospital
“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”
Budget: $296,061

Neuren Pharmaceuticals
“A Phase 2 clinical trial of trofinetide, also known as NNZ-2566, for females with Rett Syndrome ages 5-15”
Budget: $250,000

Scout Program

Daniela Brunner, PhD, PyschoGenics, Inc
“Scout Program: A Drug Discovery Screen in a Mouse Model of Rett Syndrome”
Budget: $323,271.40

2014 Research Awardees & Funded Projects

Angel Awards

Julian Paton, PhD, University of Bristol and Adrian Newman-Tancredi, PhD, Neurolixis
““NLX-101 – a novel, highly selective and potent serotonergic 5-HT1A receptor agonist for the treatment of respiratory arrhythmias in Rett Syndrome: a pre-clinical proof-of-principle study in murine models”

Budget: $300,000

Lay Description:
Abnormal breathing is a highly prevalent component of the Rett syndrome phenotype.  It presents as apneas and an irregular inter-breath pattern and is associated with significant falls in arterial blood oxygen saturation. The Paton lab submitted a pre-clinical proof of principle study in partnership with industry. This study will use integrative physiology and drug discovery to address potential treatments for breathing in this neurologic disorder.  Their specific aim is to demonstrate that stimulation of serotoninergic type 1A (5-HT1A) receptors using the novel selective agonist, NLX-101, will improve respiratory deficits in mouse models of Rett syndrome.  Additional measures of motor function, known to be impaired in Rett syndrome, will also be explored following treatment. They will compare the effects in two different strains: the ‘Bird’ strain, a MeCP2 knockout model, and the R168X strain, one of the most common mutations found in Rett patients.  In these murine models, the breathing abnormalities are highly reproducible, measurable and translatable to the human condition.  The Paton lab has recently demonstrated that the respiratory phenotype in Rett mice may be a consequence of deficiencies in inhibitory synaptic transmission in the brainstem, and less selective 5-HT1A agonists have shown functional benefits in breathing and improved survival rates.  NLX-101 has recently been granted ‘orphan drug status’ both in North America and in the European Union, an important milestone in delivering the drug to the patient.  If shown to be effective for treating the respiratory defects in Rett mice, the Paton lab will pursue clinical trial testing of NLX-101 for treatment of Rett syndrome.  In this regard, Dr. Paton has established a UK-based Rett syndrome network spanning 4 institutions and comprising at least 44 patients.  The drug, the mouse models and the clinical network make this project one which is likely to be successful.

HeART Awards

Michela Fagiolini, PhD, Boston Children’s Hospital
“Assessing NMDAr modulators to ameliorate cortical regression in Rett Syndrome”

Budget: $150,000

Lay Description:
The Fagiolini laboratory at Boston Children’s Hospital (BCH) proposes a preclinical study of two very promising modulators of the  NMDA (N-methyl-D-aspartate)receptor, a special type of glutamate receptor in brain cells.  These receptors are critical in synaptic plasticity which is important for learning and memory, and are somewhat impaired in Rett syndrome.  In December 2012, Dr. Michela Fagiolini and colleagues showed that a genetic rescue of an imbalance of NMDA receptor components found in Rett syndrome could improve cellular function and circuitry (Durand et al, Neuron 2012).  Based on this work, Dr. Fagiolini aims to target the NMDA receptor with two drug compounds in a preclinical study in the Rett mouse model.  One is FDA approved ketamine, and the second is a new inhibitor of the NMDA receptor GLYX-13.  Dr. Fagiolini will work together with Dr. Nick Andrews of BCH to evaluate the safety, pharmacokinetic activity and efficacy of each drug.  A second part of this project is to ready a potential clinical trial design should these drugs be deemed safe and efficacious in the animal model.  To this regard, she will collaborate with Dr. Walter Kaufmann, director of the Rett Syndrome Clinic at BCH, to design a clinical trial that will evaluate these NMDAR modulators as potential treatments in girls diagnosed with Rett syndrome.    This HeART award is powering an essential preclinical study so that  a quantitative, systematic and comprehensive evaluation of these drugs for safety and degree of efficacy is performed.  It is possible that the compounds could quickly move to future human clinical studies as a potential treatment of Rett syndrome, should the preclinical data show a positive and robust outcomes.

Alexander Kabanov, PhD, University of North Carolina at Chapel Hill
“Brain Delivery of BDNF via novel Nano-formulation for Treatment of Rett Syndrome”

Budget: $150,000

Lay Description:
Rett syndrome (RTT) is a rare and incurable postnatal female neurodevelopmental disorder. Growing evidence suggest increasing brain-derived neurotrophic factor (BDNF) levels in the brain could be beneficial for treatment of RTT. However, BDNF has not been practically used in clinic to treat Rett patients, because development of BDNF as therapeutics for Rett disorder is extremely challenged by BDNF poor serum bioavailability and its limited capacity to cross the blood-brain barrier (BBB).  Dr. Kabanov will tackle this challenge using an original “nanocytokine” delivery technology, which aims to greatly increase the amounts of the therapeutic protein that reaches the brain. The proposal will evaluate efficiency and safety of our approach and if successful provide proof of principle for a novel therapeutic modality of RTT that will be further advanced for clinical development.

Frank Menniti, PhD, Mnemosyne Pharmaceuticals, Inc.
“Effects of NMDA receptor modulators on network activity in a human iPSC-derived model of cortical dysfunction in Rett Syndrome”

Lay Description:
One of the effects of mutation or deletion of the MeCP2 gene is to weaken and disrupt the activity of networks in the brain’s cortex. The cortex is the part of the brain responsible for high-level cognitive and emotional functions and sensorimotor activities. In Rett patients, cortical networks are weakened and hypo-active. New therapies that restore cortical network activity are anticipated to have a broad effect, improving neurological, cognitive and emotional function. The NMDA receptor plays a principal role in orchestrating cortical development and in the regulation of cortical function throughout adulthood. Evidence indicates these functions of the NMDA receptor are disrupted by MeCP2 mutations and that this contributes significantly to cortical dysfunction in Rett. Mnemosyne Pharmaceuticals is developing a new class of drugs that modulate the activity of NMDA receptors. The aim of this HeART grant is to test these compounds for their ability to restore cortical activity in a novel in vitro model system of the cortical dysfunction in Rett developed by Dr. Alysson Muotri’s lab at UCSD. The Muotri lab creates cortex-like neuronal networks in a petri dish from human inducible pluripotent stem cells. When MeCP2 is deleted, the networks formed are hypoactive, similar to in Rett patients. They will seek an NMDA receptor modulator that restores network activity in this model system. This data will give important information on how to use this compound in further testing in Rett mouse models, on the way to a new potential therapy for Rett patients.

HeART Awards – Neuro-Habilitation

Susan Bruce, PhD, Boston College
“Sensory Integration to Increase Functional Reaching in Children with Rett syndrome and related disorders”

Budget: $136,849

Lay Description:

The four main characteristics of RTT are: loss of hand use, hand stereotypies, loss of communication and gait apraxia. Severely limited hand use is common in these children, along with sensory processing delays and compromised social development. The use of sensory, cognitive and motor stimulation through interaction with enriched environments has been shown to improve neurological foundations of functioning in mice and other species. A study by Kondo et al. (2008) demonstrated a significant positive influence of environmental enrichment on cerebellar motor learning and coordination in female mice with MECP2 mutations. Enriched environments included access to gross motor equipment and sensory objects and materials with different textures, shapes and sizes that were changed frequently to maintain novelty. Moving through this type of enriched environment promoted the development of new neurons and the maturation of existing neurons to enhance neuronal activation and signaling between neurons and to strengthen neuronal circuits in mice. This produced changes in synaptic and brain structure, and function, notably, improved motor coordination, motor learning and/or locomotor activity. The overall objective of this study is to evaluate the effectiveness of Sensory Integration (SI) to increase functional reaching in 5 students with Rett syndrome/Rett-Related Disorders to test their hypothesis that the benefits of Sensory Integration intervention improve sensory processing and motor function in children.

Pamela Diener, PhD, Marymount University and Jack Engsberg, PhD, Washington University of St. Louis
“Improving Upper Extremity Motor Skills in Children with RTT Using Selected Movements to Control Internet Virtual Reality Computer Games”

Budget: $150,000

Lay Description:

Individuals with Rett syndrome (RTT) spend the majority of their day engaged in stereotypies of handwringing/clapping and hand-mouthing. These behaviors preclude them from using their upper extremities in purposeful tasks such as schoolwork, individual and group play skills, self-feeding, bathing and other activities of daily living. The long-term goal of this project is to improve the quality of life of individuals with Rett syndrome by decreasing hand wringing/mouthing, improving self-initiated use of the upper extremities and promoting functional upper extremity play skills. The purpose of this project is to improve upper extremity motor skills in individuals with RTT using selected movements to control internet virtual reality (IVR) computer games. The expected outcome will be a novel therapeutic intervention that decreases upper extremity stereotypies that interfere with purposeful arm and hand use and promotes purposeful, goal-directed arm function and associated postural control. The long-term impact will be improved participation of children with RTT via a simple, inexpensive and motivating intervention. The rationale for the project is that the compelling nature of IVR computer games will enable us to develop new and functional movement patterns in persons with RTT such that they will use the patterns to participate more fully in life activities. Their central hypothesis is that the IVR intervention will decrease hand wringing/mouthing and increase hand and arm movements away from the cardinal sagittal body plane (i.e., center line) thereby promoting the development of more functional motor skills.

David Koppenhaver, PhD, Appalachian State University
“Investigating Visual Attention to Print in Children with Rett Syndrome”

Budget: $113,876

Lay Description:

Eye-tracking technology has been demonstrated to be a reliable means of assessing social preferences and basic cognitive performance (e.g., matching and comparison tasks) in children with Rett syndrome (RTT).  Encouraging clinical reports suggest success in using eye-tracking technology to access communication devices (e.g., “User Stories). This research and clinical advances suggest that eye-tracking technology has evolved to the point that it can be calibrated despite repeated or constant movements by children with RTT. Since they published their first study of storybook reading interactions of parents and children with RTT (Koppenhaver et al., 2001), it has been accepted that shared book reading is an effective approach to communication and emergent literacy intervention for children with RTT. What remains unknown, however, is how to measure literacy understandings or growth that may result from shared book reading interactions. The long term goal of the proposed project is to develop a reliable means of measuring increased and purposeful attention to print, directional tracking of text, and eventually sophisticated eye movements that co-occur with fluent reading in individuals with RTT.

Charles Nelson, III, PhD, Boston Children’s Hospital
“New Methods to Assess Cognition and Affect in Girls with Rett Syndrome”

Budget: $147,741

Lay Description:

Obtaining valid and objective information about cognitive function and anxiety in girls with Rett syndrome (RTT) is challenging due to limitations in girls’ language and motor function. The Nelson group seeks to evaluate cognitive function by adapting the Mullen Scales of Early Learning (MSEL) for use on a Tobii eye tracker. They propose that an adapted eye tracking MSEL, in a sample of typically developing children, will find good agreement with the conventional MSEL. They also predict that we will be able to obtain a more accurate and veridical assessment of cognitive functioning in girls with RTT and that greater clinical severity will be associated with lower eye tracking MSEL scores. Their secondary aim is to develop an index of anxiety using high density electroencephalography (EEG).  In both aims, they wish to develop what are essentially “covert” measures of girls’ cognitive ability and affective state by drawing from their lab’s expertise in eye movements and EEG. The information they obtain from these experiments will help to better understand the needs of individuals with RTT and ultimately improve their quality of life. Additionally, these measures could ultimately be extended to apply to other populations with similar verbal and or motor limitations in the future.

Sarika Peters, PhD, Vanderbilt University Medical Center
“Auditory processing, language, and learning in Rett and Rett-related disorders”

Budget: $87,852

Lay Description:

Despite significant advances at the level of basic research in Rett syndrome (RTT) that have progressed to treatment trials, the characterization of higher-level cognitive and language processes in RTT remains understudied. This is attributable, in part, to the difficulties with utilizing conventional standardized psychological assessments in RTT because they typically require hand use and/or verbal abilities and therefore are not sufficiently sensitive to capture the full range of functioning. The lack of adequate measures of functioning also poses a problem for validating outcomes of clinical trials, and for tracking progress related to language and behavioral interventions over time.  Cognitive neuroscience methods utilizing event-related-potentials (ERP), a portion of EEG time-locked to a stimulus event, have been successfully used in infants and individuals with no speech to document cognitive and language functioning, predicts developmental outcomes, and provides evidence of treatment effects without relying on overt behaviors by the participant. In RTT, neuroscience investigations thus far have focused primarily on visual processing and the use of eye gaze while participants attend to a screen on which stimuli are presented. Auditory processing has not yet been examined in RTT, yet most interventions related to communication (even if they include eye gaze devices) involve processing of auditory instructions. An advantage of using an auditory ERP approach is that it will allow for the assessment of language and cognitive functioning without extensive attentional demands (i.e., a participant having to attend to a screen) and therefore could be used in participants with wider age ranges and functional levels. Using passive auditory ERP paradigms they will (1) evaluate the ability to discriminate speech from nonspeech, (2) examine auditory learning without visual cues, and (3) assess the extent of attention to auditory input using name recognition in 30 participants between the ages of 4-10 years. Their hypothesis is that ERP evidence of greater stimulus condition differences will be associated with caregiver reports and standardized language and behavioral scores indicating higher functioning in communicative and social domains.  Completion of this study would have exceptional impact for RTT and MECP2 duplication syndrome because it will: 1) provide novel, objective, brain-based measures for tracking clinical severity and development of higher level cognitive and language functions in these disorders, 2) assist in determining whether auditory modalities could be effective for interventions and facilitating learning, and 3) provide a sensitive measure of social/emotional processing to compare/contrast with parental reports of emotional/behavioral functioning. In addition, this approach will have applicability to other populations of children who are nonverbal and who have motor impairments that limit the generalizability of more conventional standardized tests.

HeART Awards – Scout Program

Bianca De Filippis, PhD, Istituto Superiore di Sanita, Italy
“Preclinical evaluation of the bacterial protein CNF1 as a novel therapeutic approach for Rett syndrome”

Budget: $74,800

Lay Description:

Proteins belonging to the RhoGTPases’ family, including Rho, Rac and Cdc42 subfamilies, are crucial molecules in neuronal plasticity and cognition, critically involved in several intellectual disabilities. By cycling between an active GTP-bound state and an inactive GDP-bound state, Rho GTPases integrate extracellular and intracellular signals to coordinate dynamic changes in the actin cytoskeleton, thereby stimulating a variety of processes, including morphogenesis, migration, neuronal development, cell division and adhesion. Rho GTPases can be transiently shifted in their activated state by a bacterial toxin, named CNF1, through deamidation of critical glutamines. CNF1 brain inoculation induces a re-arrangement of cerebral actin cytoskeleton, enhances neurotransmission and synaptic plasticity and improves learning and memory performance in mice. Moreover, stimulation of brain structural rearrangements by CNF1 was found to reinstate experience-dependent plasticity in adult age, thus suggesting that Rho GTPases activation may be exploited to promote brain repair. The De Filippis laboratory has demonstrated that a single intracerebroventricular (icv) administration of an Escherichia coli toxin, the CNF1, markedly improved the behavioral phenotype of MeCP2-308 male mice and dramatically reversed the evident signs of atrophy in astrocytes in a mouse model of Rett syndrome (RTT). The main aim of this proposal is generating robust preclinical findings to enhance the predictive value of our translational research. The CNF1 treatment will be thus further investigated, to substantiate its efficacy in reversing RTT-related abnormalities in two different mouse models and in female mice.

Maurizio Giustetto, PhD, University of Torino, Italy
“Restoring the AKT/mTOR pathway to Treat Rett syndrome”

Budget: $74,998

Lay Description:  

There is mounting evidence showing aberrant neuronal protein synthesis as one underlying cause of the clinical features of autism spectrum disorders. Interestingly, the regulation of protein synthesis via mTOR/PI3K pathway is crucially involved in synaptic function, structure and plasticity. In post mitotic neurons mTOR activity and its downstream targets can control the size of the neuronal cell soma, axon path finding and regeneration, dendrite arborization, dendritic spine morphology and synaptic plasticity, all aspects altered in Mecp2 mutants. The Giustetto lab has recently proposed that RTT may be due to hypofunctioning protein synthesis in brain cells. They have shown that both protein synthesis and the translation-related intracellular signaling are affected both in Mecp2-KO male mice and in Mecp2 heterozygote female mutants that better mimic the human disease. These data are at the basis of the key concept underlying this project: ameliorating the development of RTT deficits by correcting the deficits of protein synthesis and translation-related intracellular signaling in Mecp2 mutant mice. The candidate treatment proposed here is the administration of inhibitors of the phosphatase and tensin homolog (PTEN), a protein that acts as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-triphosphate (PIP3) resulting in the inhibition of the AKT signaling pathway. PTEN is very close to mTOR in the signaling cascade controlling protein synthesis and it could therefore have more direct action on this pathway than other treatments, such as extracellular ligands of growth factor receptors, upstream of the AKT/mTOR cascade.  Their specific aim is to evaluate whether interventions aimed at restoring defective protein synthesis may arrest or ameliorate the behavioral, morphofunctional and molecular alterations present in Mecp2 mutant mice. They will treat both presymptomatic and symptomatic MeCP2 mutant mice with Vo-OHpic to test its effectiveness: i) as a preventive therapy; ii) in producing partial or complete signs regression in diseased mutants.  The results of these experiments will pave the way to the identification of other targetable pathways and novel therapeutic approaches.

Lucas Pozzo-Miller, PhD, The University of Alabama at Birmingham
“Analogs of (1-3)IGF-1 (glypromate) for the improvement of hippocampal dysfunction in female Mecp2 heterozygous mice: a preclinical trial for Rett syndrome”

Budget: $75,000

Lay Description:

Numerous studies in animal models of RTT have revealed dysfunctions of neuronal and network excitability in Mecp2 deficient mice. The Pozzo-Miller lab previously shown that the specific regions of the hippocampus from symptomatic male Mecp2 knockout (KO) mice are hyperactive, which leads to hippocampal dysfunction, saturation of synaptic plasticity, and seizure disorders, all of which are common in male Mecp2 KO mice and RTT individuals.

Systemic peripheral treatment of male Mecp2 KO mice with (1-3)IGF-1 (GPE), the N-terminal tripeptide cleaved from full-length IGF-1 in the brain, significantly improved several RTT-like symptoms and increased neuronal spine density. As we know, NNZ-2566 is a GPE analogue that is already in clinical trial for treatment of traumatic brain injury, Fragile X Syndrome and RTT. Treatment with NNZ-2566 has recently been reported to protect against neuroinflammation and apoptosis, post-injury seizures, as well as correct deficits in synaptic function in rat models of hypoxic-ischemic brain injury and penetrating ballistic-like brain injury.

Here, they propose to evaluate the therapeutic efficacy of NNZ-2566 in female Mecp2 Het mice with regards to hippocampal function, with the hope of deepening our understanding of its brain sites of action, and to further inform current and future clinical trials in RTT.

Basic Research Grants

Michael Brenowitz, PhD, Albert Einstein College of Medicine
“A biophysical basis for cellular and developmental regulation by MeCP2”

Budget: $100,000

Lay Description:
The disabilities that are manifest in neurological and developmental disorders such as Rett syndrome result from the interplay among many cellular processes but start from a single event; a change in the ability of a particular protein to bind to molecular ‘marks’ imprinted on our genome. Dr. Brenowitz’s proposed studies of the methyl-CpG-binding protein 2 (MeCP2) explore the hypothesis that normal neuronal development and function requires the protein to balance recognition of epigenetic marks with binding to genomic DNA and explores how Rett syndrome mutations alter this balance. They have recently discovered that the ions whose concentrations change during neuronal development regulate DNA binding by MeCP2. This link between MeCP2 function and the nature of the neuronal environment may play a role in orchestrating MeCP2-mediated regulation of metabolism and development.

Darren Goffin, PhD, University of York
“Sensory Neural Network Alterations in Rett Syndrome”

Budget: $49,500

Lay Description:
The age-dependent symptoms in Rett syndrome is believed to arise due to alterations in the network activity of neurons in the brain. Increasing evidence suggests that the alterations in the how the brain processes sensory information may play a prominent role in the etiology of these disorders. This project is aimed at directly identifying the neuronal networks responsible for, and the immediate behavioral consequences of altered sensory information processing. Furthermore, this project will examine potential therapeutic strategies to ameliorate sensory information processing deficits in mouse models of Rett syndrome.

Peng Jin, PhD, Emory University
“Consequences of altered DNA Methylation/hydroxymethylation caused by the loss of MeCP2 in neurons”

Budget: $100,000

Lay Description:
Rett syndrome (RTT) is caused by the de novo mutations in MECP2 gene, which encodes MECP2 protein that is particularly abundant in neurons and binds specifically to methylated DNA throughout the genome. There is an ample amount of evidence supporting that MeCP2 contributes to dynamic DNA methylation and proper neuronal function. The Jin lab has profiled the whole-genome DNA methylation at base-resolution for disease-relevant neurons in a murine model of RTT, and identified many differentially methylated regions (DMRs). Based on extensive bioinformatic analyses, they have identified a distinct set of transcription factors (TFs) whose binding to DNA may be altered in the absence of Mecp2. The Jin lab will use biochemistry, molecular biology, next generation sequencing and bioinformatics tools to determine whether the loss of Mecp2 could alter the binding of these TFs to the loci containing DMRs and then change the gene expression at these loci. This study will help elucidate the contribution of altered dynamics of DNA methylation to the pathogenesis of RTT.

Jonathan Kipnis, PhD, University of Virginia
“Immune pathology and bone marrow transplantation in disorders of MeCP2 overexpression”

Budget: $100,000

Lay Description:
Recurrent respiratory infections are a major cause of suffering and death in MeCP2-duplication syndrome patients, the majority of whom are young boys. Treating these infections is difficult, and the reason for this is poorly understood. This project is focused on understanding why MeCP2-duplication syndrome patients are at risk for life-threatening infections and inflammation, and will potentially lead to immune-based treatments for these patients.  Using a mouse model of MeCP2-duplication syndrome, Dr. Kipnis’ laboratory is studying the response to influenza virus infection. Preliminary findings show that mice overexpressing MeCP2 are more susceptible to influenza infection, and that most aspects of the adaptive immune system are significantly impaired. In addition, they find increased populations of certain innate immune cells in the lungs of infected mice. This project is aimed at understanding 1) why the adaptive immune response, including both T and B cells, is impaired in the context of MeCP2 overexpression; 2) the potential role of innate immune cells in increased susceptibility and death; and 3) the possibility of preventing pathology through bone marrow transplant, cell transfers, or cell depletion approaches.

Lucas Pozzo-Miller, PhD, The University of Alabama at Birmingham
“Inhibitory interneuron dysfunction in network activity in female Mecp2 mice”

Budget: $100,000

Lay Description:
Unbalanced excitation/inhibition ratio (E/I) has emerged as a common feature in several neurodevelopmental disorders, including RTT, autism-spectrum disorders, Tourette and Down syndromes. The Pozzo-Miller laboratory has shown that the E/I imbalance in the hippocampus of Mecp2 knockout mice is due to impaired inhibition, and leads to heightened neural network activity, enhanced excitatory synaptic transmission and impaired synaptic plasticity, which will result in seizure disorders and intellectual disability in RTT. However, how GABAergic inhibitory interneurons contribute to those altered features of hippocampal function remains to be defined. Their hypothesis is that impaired synaptic function from and onto GABAergic inhibitory interneurons in area CA1 of the hippocampus of female Mecp2 heterozygous mice affects synaptic plasticity and gamma-band oscillations of neuronal activity. Detailed characterization of these hippocampal features will provide a deeper understanding of RTT pathophysiology and provide useful biomarkers for preclinical studies of novel therapies.

Mentored Training Fellowships

Breanne Byiers, PhD, University of Minnesota
“Assessing oculomotor function in Rett syndrome using integrated EEG and eye tracking technology”

Budget: $98,751

Lay Description:
Eye tracking has been proposed as a way for individuals with Rett syndrome (RTT) to bypass the characteristic verbal and motoric deficits associated with the syndrome and demonstrate the full range of their language and cognitive skills. Many of the circuits responsible for voluntary limb motor movements are also involved in the production eye movements, however, it is currently unclear whether patterns of eye movements among individuals with RTT differ from those of the general population. Understanding how the oculomotor system is functioning among individuals with RTT will have important clinical implications for the use of eye tracking technology in assistive devices for communication and environmental control, and for clinical and research assessments of cognitive function and learning. In addition, by revealing the degree to which cortical circuitry responsible for eye movements is impaired in RTT, the results may lead to the development of new, non-invasive outcome measures of cortical function for use in clinical trials. This project will use state-of-the-art eye tracking technology that has been integrated with high-density electroencephalography (EEG) to assess functioning of the oculomotor system in individuals with RTT.

Claudia Fuchs, PhD, University of Bologna, Italy
“Drug Therapy Targeted to Core Molecules in Neural Plasticity Cascades: A Promising Tool for the CDKL5 Variant of Rett Syndrome”

Budget: $100,000

Lay Description:
Mutations in the CDKL5 gene were originally found in individuals diagnosed with the early-onset seizure variant of Rett syndrome (RTT). The CDKL5 variant of RTT is a very severe chronically debilitating disorder that preferentially affects girls. Most of the children affected by this disorder suffer from seizures that begin in the first few months of life. Most cannot walk, talk or feed themselves, and many are confined to a wheelchair. Many also suffer from scoliosis, visual impairment, sensory issues and various gastrointestinal difficulties. The severity of this disease impacts heavily on the quality of life of families, as well as on health care systems. Currently, there is no cure or effective treatment for CDKL5 disorder, and the mainstay of care for this disorder is support for the families. Therefore, the identification of therapies for CDKL5 disorder represents an important social challenge. Using a mouse model that mimics the CDKL5 disease, we recently showed a causal link between the neuroanatomical alterations due to Cdkl5 loss-of-function and derangement of the AKT/GSK3beta pathway, an important pathway in brain development. Based on these premises, Dr. Fuchs’ hypothesis is that drugs targeting core molecules in the AKT/GSK3beta signaling pathway may be potential therapeutic targets for the improvement of the neurological phenotype in patients with the CDKL5 variant of RTT.

Janine Lamonica, PhD, University of Pennsylvania
“Targeting Protein Degradation Pathways to Treat RTT”

Budget: $100,000

Lay Description:
Rett syndrome (RTT) is a severe brain disorder affecting many aspects of learning, mobility, speech, and social interaction.  This disease results when there are mutations in a gene that encodes for a particular protein, MeCP2, causing it to no longer function correctly.  Many RTT patients have MeCP2 mutations that disrupt a part of the protein that allows it to bind to DNA.  Interestingly, the Zhou laboratory has found that MeCP2 mutations that disrupt DNA binding also lead to reduction in the overall levels of MeCP2 protein.  This reduction in protein levels correlates with symptom progression.  The Zhou lab wondered what would happen if the levels of the mutant protein were increased.  Therefore, they used genetic tools to increase the levels of the mutant MeCP2 protein in male mice.  Surprisingly, mice with increased mutant protein live longer and have improved movement, motor coordination, and breathing.  Since RTT is a female disorder, I plan to repeat the same genetic experiment in female mice to test whether this finding might be applicable to female RTT patients.   Unfortunately, it is not possible to use the same genetic strategy to increase MeCP2 levels in human patients.  Therefore, Dr. Lamonica plans to identify proteins that normally help to decrease the amount of MeCP2 protein produced in cells.  Once identified, she hopes to find drugs that inhibit these proteins, which would ultimately allow more MeCP2 protein to be produced, and, hopefully, alleviate symptoms.

William Renthal, MD, PhD, Harvard Medical School
“Characterization of a Novel Activity-Dependent Phosphorylation Site on MECP2”

Budget: $100,000

Lay Description:
Rett syndrome is a severe neurological disorder characterized by developmental delay, seizures, and autism spectrum behavior. It has been known for over ten years that mutations in a single gene, MECP2, cause this syndrome, but it has been challenging to understand how these mutations lead to such severe neuronal and behavioral abnormalities. It is currently not possible to correct the genetic mutations directly in every brain cell, so it is important understand how MECP2 functions in order to rationally design new therapies for Rett syndrome patients. The Greenberg laboratory has recently discovered a new site on the MeCP2 protein that is modified in response to neuronal activity. They believe this modification is important to Rett syndrome because a patient with a mutation at this same site has been reported. This modification process, called phosphorylation, is often used to change the way a protein functions in the cell, and my mentored research proposal aims to understand precisely how this occurs with MeCP2. Dr. Renthal hypothesizes that phosphorylation of the novel site we discovered on MeCP2 functions to remove it from DNA and permit activation of gene programs essential for neuronal circuit formation. Therefore, he believes that when MeCP2 is mutated, neuronal activity cannot initiate the necessary gene programs, and ultimately result in abnormal neuronal circuitry, seizures, and autism spectrum behavior. The proposed studies will lead to better understanding of the molecular function of MeCP2 phosphorylation as well as the gene programs it regulates, thus informing multiple new directions for rational therapeutic design.

Xin Xu, PhD, The University of Alabama at Birmingham
“Molecular Mechanisms of Homeostatic Synaptic Plasticity in Mecp2 KO Neurons”

Budget: $100,000

Lay Description:
Numerous studies in animal models of Rett syndrome (RTT) have revealed over-excitation of neuronal activity. Negative-feedback homeostatic synaptic plasticity, also known as synaptic scaling, maintains the global synaptic strength of individual neurons in response to sustained alterations in neuronal activity. This cell-wide homeostatic balance is critical to stabilize neuronal network. The Pozzo-Miller laboratory discovered an imbalance of synaptic excitation and inhibition in the hippocampus of symptomatic male Mecp2 knockout (KO) mice. Since this balance is thought to be maintained by homeostatic mechanisms, they hypothesize that restoring homeostatic synaptic plasticity will ameliorate neurological deficits in RTT. They propose to define the role of MeCP2 in homeostatic synaptic plasticity, and identify which of the known molecular mechanisms responsible for synaptic scaling are affected by Mecp2 deletion. The best-characterized mechanism of homeostatic synaptic plasticity is the regulated trafficking into and out of synapses of the glutamate receptors. Dr. Xu will focus on two proteins that are responsible for the insertion and removal of glutamate receptors from synapses. By characterizing their role during homeostatic synaptic plasticity in Mecp2 KO neurons, she will provide novel targets for improving hippocampal function in RTT.

Database Contracts

John Christodoulou, AM, Sydney Children’s Hospital Network, Australia
Budget: $100,000

Helen Leonard, MBChB MPH, The University of Western Australia
Budget: $100,000

New Research Program

Rett Syndrome Rat Model Working Group
Budget: $36,500

  • Daniela Brunner, PhD, PyschoGenics, Inc
  • Chun Jiang, PhD, Georgia State University
  • Michelle Olsen, PhD, The University of Alabama at Birmingham
  • Lucas Pozzo-Miller, PhD, The University of Alabama at Birmingham
  • Rodney Samaco, PhD, Baylor College of Medicine

Supplemental Funding to Current Projects

Daniela Brunner, PhD, PyschoGenics, Inc
“Scout Program: A Drug Discovery Screen in a Mouse Model of Rett Syndrome”
Budget: $71,212.35

Walter Kaufmann, MD, Boston Children’s Hospital
“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”
Budget: $142,939

Daniel 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”
Budget: $184,409

2013 Research Awardees & Funded Projects

HeART Awards

Theresa Bartolotta, Ph.D, Seton Hall University and Patricia Remshifski, Ph.D, Monmouth University
“Eyetracking in Rett syndrome: A preliminary investigation of receptive and expressive vocabulary”

Budget: $60,000

Lay Description:
Individuals with Rett syndrome (RTT) have significant communication difficulties. Inability to use speech and loss of effective hand movements makes it difficult for individuals with RTT to express thoughts and ideas. It is challenging for clinicians and educators to assess cognition and language skills in these individuals because of their complex communication and physical needs. Eye tracking technology has recently been demonstrated to be a reliable tool to measure cognitive abilities, including attention and perception, for this population, and may enable individuals with RTT to access communication devices. The purpose of this study will use eye tracking technology to explore two goals with persons with RTT: (1) to assess receptive vocabulary; and (2) to train use of vocabulary items to convey basic requests for communication of daily needs.  This research project will make a difference in the lives of persons with RTT by providing needed information regarding receptive language skills. The investigators also expect to discover the clinical relevance of eye tracking technology for communication in persons with RTT.

John Christodoulou, AM,  The Children’s Hospital at Westmead
“Preclinical Evaluation of Tubastatin A, a Novel Therapy for Rett Syndrome”

Budget: $150,000

Lay Description:
Rett syndrome (RTT) is a genetic neurological disorder, primarily affecting girls, and is mostly caused by mutations in the MECP2 gene. As the biological processes that are disturbed in RTT have become better understood, a small number of specific drugs that could have a beneficial effect on some components of the disease have been identified. However, as yet, there is no cure for RTT. In this research project, the investigators plan to investigate the therapeutic advantage of the inhibitory drug tubastatin A on the Mecp2T158A RTT mouse model.  Tubastatin A has been shown to be effective in cell based and animal models of a number of diseases that affect brain development and function.  In the Christodoulou laboratory, they have observed brain cells from the Mecp2T158A RTT mouse model have increased levels of histone deacetylase 6 (HDAC6), the target molecule of tubastatin A. Therefore, it is feasible to assume that the treatment with tubastatin A may restore HDAC6 levels to normal and in turn improve or perhaps even reverse the neurological problems associated with RTT. They will test the capacity of tubastatin A to return the breathing, and behavioural deficits observed in the Mecp2T158A mice towards normal. As a consequence of these studies, they hope to identify a safe and effective drug that could be used in future RTT patient clinical trials.

Steven Gray, PhD,  University of North Carolina at Chapel Hill
“BDNF gene transfer for the treatment of Rett syndrome”

Budget: $150,000

Lay Description:
BDNF is underexpressed in Rett (RTT) mouse models, and this has been linked to the RTT phenotype.  Introduction of BDNF into RTT mice using genetic models, exogenous delivery of recombinant protein, or small molecule mimics has been shown to be therapeutic. However, the inability to deliver BDNF to the central nervous system (CNS) in a practical and sustainable manner is a major obstacle to the translation of a BDNF therapy to humans.  Dr. Gray proposes to use vector-mediated gene transfer as a means to deliver BDNF to the CNS in a sustained and translatable manner.  The objectives of this HeART proposal are to 1) identify the optimal gene delivery approach to express the optimal therapeutic dose of BDNF across the CNS, 2) identify if chronic expression of BDNF leads to adverse effects, and 3) test for efficacy in the female RTT mice to best predict therapeutic outcomes in relevant human populations.  The overall objective of this study is to determine if a BDNF gene transfer approach is safe, effective, and practical for consideration as a future human therapy for RTT.

Jeannie Lee, MD, PhD, Massachusetts General Hospital
“Treating Rett syndrome via selective reactivation of the silenced MECP2 allele”

Budget: $149,600

Lay Description:
Dr. Lee’s proposed research will develop a novel method of treating Rett syndrome (RTT) by reactivating the silent Mecp2 allele. They aim to do so by extending technical innovations to the original “RNA-activation” technology developed in their laboratory (RNA-a; patent pending, PCT-US2011-065939). In the pharmaceutical industry, current therapeutic strategies focus almost exclusively on protein and microRNA targets. Yet, the Lee lab has shown that long noncoding RNAs (lncRNAs) confer a temporal and spatial specificity not possible with proteins and small RNAs.  To this end, Dr. Lee has developed therapeutic strategies that effectively targeted the lncRNA.  By designing oligonucleotide drugs that targeting the inactive X chromosome (Xi) in Rett syndrome would circumvent the effects where the mutant MeCP2 is being expressed.  Dr. Lee’s lncRNA targeting strategy would reawaken epigenetically silenced genes by disrupting binding and reawaking the repressed normal MeCP2.  To date, X-linked disease genes have been difficult to treat because of many layers of heterochromatin resulting from X-chromosome inactivation (XCI).  The Lee laboratory has specialized in the study of XCI for the past 16 years and recently discovered X-linked elements involved in the spreading of XCI along the Xi. From these discoveries, they hypothesize that it should be possible to selectively reawaken the silenced Mecp2 allele, without reactivating most or all of the Xi. Indeed, reactivating the entire Xi would be undesirable, as they have shown that global X-reactivation results in cancer. Herein they propose to achieve this by leveraging gene-specific control elements along the Xi to reactivate the normal Mecp2 gene.

Basic Research Grant Recipients

Kerry Delaney, PhD, University of Victoria
“Imaging dynamics of cortical neuron dendritic spines in female heterozygous Rett mouse brain”

Budget: $100,000

Lay Description:
The gene that causes Rett syndrome is located on the X chromosome.  Females have two X chromosomes but in each cell only one is active.  This choice of which chromosome will be active occurs randomly, very early in development.  Thus all tissues, the brain included, are comprised of a mosaic of cells that express genes on the X chromosome from either their father or mother.  Thus brain circuits are made up of some cells with a working copy of the Rett gene, some with a non-working copy.  The Delaney lab’s goal is to understand how neurons with a non-working Rett gene function in neural circuits.  Normally our brains are plastic. In response to new environments and learning challenges, brain cells modify existing synapses, make new ones and undo old ones.  Is this turnover of synapses happening normally in a Rett brain?  When stimulated to increase the turnover of synapses, will neurons lacking a working Rett gene respond normally?  If not, can these neurons be “woken up” and induce them to form stable synapses?  The Delaney lab will label neurons fluorescently in live female mouse brains to follow the persistence or turnover of the spines on their branches where synapses are made.  Using another label, they can determine which Rett gene is active, functional or non-functional in each cell and thereby follow the behavior of the synapses in the two cell types. Eventually they will use treatments to improve synapse formation to determine whether they work on the deficient neurons without disrupting the normal ones.

Serena Dudek, PhD, National Institute of Environmental Health Sciences
“Role of IGF1R in hippocampal CA2 plasticity and function: interaction with MeCP2”

Budget: $98,000

Lay Description:
An increasing number of observations by the Dudek laboratory contribute to their compelling hypothesis that hippocampal area CA2 is a key module for processing social information for certain forms of memory.   Of note, neuron size in the CA2 is decreased in a mouse model of Rett Syndrome.  The Dudek lab proposes to study synaptic plasticity in hippocampal area CA2 in response to activation of a target receptor for a compound reported to be in clinical tests for humans with Rett Syndrome: Insulin-like growth factor 1 (IGF-1).  The receptor for this growth factor, igf1r, is highly enriched in the CA2 area of the mouse hippocampus, over all other areas of the brain.  Therefore, they propose to study the effects of IGF-1 on CA2 pyramidal neurons of wild-type and MeCP2 mutant mice. Independent of the results of the human trials, they expect the results of the proposed work will inform researchers on how animal models will best be used for screening growth-factor related therapeutic agents and could be transformative for our understanding of Rett syndrome.

Xinyu Zhao, PhD, University of Wisconsin-Madison
“Restoring network integration of MeCP2-deficient neurons”

Budget: $100,000

Lay Description:
MeCP2 is known to be important for neuronal development. However critical questions remain concerning the roles of MeCP2 in neural circuitry formation: How does MeCP2 deficiency affect neuronal network wiring? Does MeCP2 regulate neural network formation through cell-autonomous mechanism? Can enhancing BDNF or IGF-1 signaling restore the neural network wiring of MeCP2-deficient neurons?  The goal of this proposal is to determine how MeCP2 deficiency affects neuronal network formation and whether such deficit can be restored by enhancing BDNF.  Dr. Zhao has demonstrated that MeCP2 deficiency leads to impaired neuronal maturation, dendritic complexity, and dendritic spine density. However how morphological deficits of MeCP2-deficient neurons affect their network wiring is unknown. In addition, they have shown that MeCP2 regulates neuronal development through small noncoding microRNAs (miRNAs).   They have discovered that inhibition of miRNA-15 family miRNAs rescues dendritic complexity in MeCP2-deficient neurons.  Their data suggest that miR-15 might be a novel treatment target for RTT. Whether enhancing BDNF levels through miR-15 inhibition can restore neuronal network integration of MeCP2-deficient neurons remains to be determined. Furthermore, they have established novel pseudo typed rabies virus (RaV)-based retrograde mapping and “CLARITY” transparent brain imaging methods that allow us to assess neuronal network in unprecedented scales and details.  To this end, they will test the hypothesis that MeCP2 deficiency alters neuronal network wiring, which may be restored by BDNF enhancement. To test this hypothesis, they will determine the impact of MeCP2 deficiency on neural network wiring (Specific Aim 1); and will determine whether BDNF enhancement can restore neuronal wiring deficit resulted from MeCP2 deficiency (Specific Aim 2). Their work will bridge a major gap in our knowledge about MeCP2. This network assessment may unveil possible reasons and potential solutions for the partial effects of different drugs on Rett models.

Mentored Training Fellowship Recipients

Rocco Gogliotti, PhD, Vanderbilt University Medical Center
“Temporal divergence of hypoconnectivity and excitotoxicity in Rett syndrome”

Budget: $100,000

Lay Description:
Rett syndrome is a postnatal neurological disorder that results from deletions, mutations or duplications in the methyl CpG binding protein (MeCP2) gene.  In the clinic, young Rett patients undergo a period of rapid developmental regression, coupled with uncontrolled repetitive movements and social anxiety.  Patients then experience a plateau phase, followed by the gradual presentation of hypokinetic movements, scoliosis and muscle weakness late in disease.  This biphasic presentation indicates that multiple mechanisms may govern disease progression in Rett syndrome, some early and acute, and others more chronic in nature.  Dr. Gogliotti’s goal is to assess both the efficacy and the adverse effect liability of therapeutics designed to modulate glutamatergic neurotransmission in the face of the temporally divergent elements of Rett syndrome.  Specifically they will utilize positive and negative allosteric modulators (PAMs and NAMs) of the metabotropic glutamate receptor 5 (mGlu5) subtype.  mGlu5 is a post-synaptic glutamate receptor that is a core regulator of excitatory neurotransmission and long-term forms of synaptic plasticity, and as such, is believed to have therapeutic potential for disease like Rett syndrome these properties are disrupted.  Unfortunately, mGlu5 drug discovery has been plagued by the presence of adverse side effects, including seizures, which have hindered pre-clinical assessments of efficacy.  Dr. Gogliotti has demonstrated that mGlu5 signaling has resulted in the development of compounds free from seizure liability, even in the hypersensitive situations like the Mecp2-/y model of Rett syndrome.  Furthermore, they have shown that one of their novel mGlu5 PAMs, VU0462807, both rapidly and significantly ameliorates advanced stage Rett phenotypes in mice.  They propose to phenotypically and pathologically expand on this data to assess the potential for mGlu5 PAMs as therapeutics for advanced stage Rett syndrome.  Conversely, given that failed synaptogenesis in Rett syndrome is believed to be due to excitotoxicity, they will also assess the risk for mGlu5 PAMs to intensify developmental regression phenotypes when administered to young Rett mice.  Likewise, they anticipate that peri-natal treatment with the mGlu5 NAM MTEP will normalize neurotransmission during developmental regression, thereby pharmacologically uncoupling the early and late stages of Rett syndrome in mice.   While they propose to use mGlu5 modulators to highlight the biphasic elements of Rett syndrome, it is important to note that the results from this study will be applicable with other Rett therapeutics, such as NMDAR modulators, where normalization of neurotransmission is also the proposed mechanism.  In that regard they contend that this proposal holds broad impact from both basic science and translational perspectives, and thus will be beneficial to the entire Rett syndrome research community.

Felipe Santos de Oliveira, PhD, University of Victoria
“Neurophysiology of cortical neurons in heterozygous female Rett mouse brain”

Budget: $100,000

Lay Description:
Because Rett syndrome is associated with a gene on the X chromosome the resulting expression of the mutant in all tissues, the brain included, is a mosaic of cells that express either a working (MeCP2+) or a non-working (MeCP2-) copy of the gene. Thus brain circuits are made up of some cells some with MeCP2+, some with MeCP2-.  Dr. Moradpour’s goal is to understand how neurons with MeCP2- function in neural circuits compared to neurons with MeCP2+.  For this work they use mice that have been engineered to have a green fluorescent marker in their nuclei that indicates which cells have MeCP2+. They then visualize and record from individual MeCP2+ (green) and MeCP2- (non-green) neurons while activating inputs from other groups of neurons to determine their average strength of their connection to the local neural circuits.  To specifically study synapses made by and to MeCP2- neurons, they will find and stimulate individual MeCP2+ and MeCP2- neurons connected to other MeCP2+ and MeCP2- neurons to determine whether there are problems with either the frequency of connections or the strength of each input.  Information of this sort is vital to rationally develop drug treatments.  For example to suggest whether a strategy should target increased release of transmitter for existing contacts or enhance the formation of more contacts and whether strategies that would affect both MeCP2+ and MeCP2- neurons would be expected to improve or worsen circuit function.

The Hospital For Sick Children, Toronto
“Post-transcriptional control of MECP2 expression during human development and disease”

Budget: $100,000

Lay Description:
The methyl CpG-binding protein gene – MECP2, encodes a protein to modulate adequate production of many other genes during neurodevelopment.  Indeed, animal models as well as human patients with incorrect balance of MECP2 protein during development and throughout the life display a wide range of neurological dysfunction.  So far, most of the mechanisms they know that keep the correct balance of MECP2 protein during neurodevelopment are related to the events associated with the production of MECP2 mRNAs, that are intermediate moieties that carry the information to produce of the protein that ultimately carries the actual biological function. However, previous published data show that the changes in the production of the MECP2 mRNAs are not sufficient to account for the changes in protein abundance during neurogenesis. Many different mechanisms are known to be involved in the steps after mRNA generation and can drastically impact the protein abundance regardless of the initial rate of mRNA production. These mechanisms can for example regulate how long the mRNAs will stay in the cellular environment and how efficient they will produce the proteins which they carry the information to. Nonetheless, and despite the evidence collected so far, none of these mechanism have been explored.  In this project Dr. Rodrigues proposes to investigate investigate the previously unexplored pathways that will help to understand the mechanisms and provides means to learn how to manipulate those levels toward normal conditions.

New Programs

Scout Program
Daniela Brunner, PhD, PsychoGenics, Inc.

Budget: $600,000

Supplemental Funding for Existing Clinical Trial Awards

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”

Budget: $184,250

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.