Research Awardees 2014

Select a category below to view our current grant recipents or select a year to view grants from 2013, 2012, 2011 or 2010.

Research Awardees: 2014

Angel Awards
HeART Awards
HeART-Neuro-Habilitation
HeART-Scout Program
Basic Research
Mentored Training Fellowships
Database Contracts
New Research Program
Supplemental Funding to Current Projects

Angel Awards

Julian Paton, PhD, University of Bristol and Adrian Newman-Tancredi, Neurolixis

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.

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HeART Awards

Michela Fagiolini, PhD, Boston Children’s Hospital
Alexander Kabanov, PhD, University of North Carolina at Chapel Hill
Frank Menniti, PhD, Mnemosyne Pharmaceuticals, Inc.

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.

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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.

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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.

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HeART Awards – Neuro-Habilitation

Susan Bruce, PhD, Boston College
Pamela Diener, PhD, Marymount University and Jack Engsberg, PhD, Washington University of St. Louis
David Koppenhaver, PhD, Appalachian State University
Charles Nelson, III, PhD, Boston Children’s Hospital
Sarika Peters, PhD, Vanderbilt University Medical Center

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.

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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.

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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.

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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.

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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.

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HeART Awards – Scout Program

Bianca De Filippis, PhD, Istituto Superiore di Sanita, Italy
Maurizio Giustetto, PhD, University of Torino, Italy
Lucas Pozzo-Miller, PhD, The University of Alabama at Birmingham

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.

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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.

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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.

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Basic Research Grants

Michael Brenowitz, PhD, Albert Einstein College of Medicine
Peng Jin, PhD, Emory University
Jonathan Kipnis, PhD, University of Virginia
Lucas Pozzo-Miller, PhD, The University of Alabama at Birmingham

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.

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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.

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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.

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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.

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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.

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Mentored Training Fellowships

Breanne Byiers, PhD, University of Minnesota
Claudia Fuchs, PhD, University of Bologna, Italy
Janine Lamonica, PhD, University of Pennsylvania
William Renthal, MD, PhD, Harvard Medical School
Xin Xu, PhD, The University of Alabama at Birmingham

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.

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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.

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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.

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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.

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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.

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Database Contracts

John Christodoulou, AM, Sydney Children's Hospital Network, Australia
“RettBASE”
Budget: $100,000

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

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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

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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

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