Research Awardees: 2013

HeART Awards
Basic Research Grant Recipients
Mentored Training Fellowship Recipients
New Programs
Supplemental Funding for Existing Clinical Trial Awards

HeART Awards

Theresa Bartolotta, PhD, Seton Hall University and Patricia Remshifski, PhD, Monmouth University
John Christodoulou, AM, The Children’s Hospital at Westmead
Steven Gray, PhD, University of North Carolina at Chapel Hill
Jeannie Lee, MD, PhD, Massachusetts General Hospital

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.

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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.

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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.

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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.

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Basic Research Grant Recipients

Kerry Delaney, PhD, University of Victoria
Serena Dudek, PhD, National Institute of Environmental Health Sciences
Xinyu Zhao, PhD, University of Wisconsin-Madison

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.

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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.

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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.

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Mentored Training Fellowship Recipients

Rocco Gogliotti, PhD, Vanderbilt University Medical Center
Felipe Santos de Oliveira, PhD, University of Victoria
Deivid Rodrigues, PhD, The Hospital For Sick Children, Toronto

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.

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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.

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Deivid Rodrigues, PhD, 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.

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New Programs

Scout Program
Daniela Brunner, PhD, PsychoGenics, Inc.

Budget: $600,000

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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.

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