Funded Projects

Select a category below to view our current grant recipents or select a year to view grants from 2014, 2013, 2012, 2011 or 2010.

Research Awardees: 2015

Angel Awards - Read-Through Program
HeART-Neuro-Habilitation
HeART Awards
Basic Research
Mentored Training Fellowships
Clinical Trial Funding
Scout Program

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.

Angel Awardees List | Back to Top

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 | Back to Top

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 - Neuro Awardees List | Back to Top

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.

Heart Awardees List | Back to Top

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.

Heart Awardees List | Back to Top

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.

Heart Awardees List | Back to Top

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.

Heart Awardees List | Back to Top

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 | Back to Top

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.

Basic Awardees List | Back to Top

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.

Basic Awardees List | Back to Top

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.

Basic Awardees List | Back to Top

 

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.

Mentored Training Fellowships | Back to Top

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.

Mentored Training Fellowships | Back to Top

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.

Mentored Training Fellowships | Back to Top

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.

Mentored Training Fellowships | Back to Top

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

Back to Top

Scout Program

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

Back to Top