We want you to know where your donation goes! It goes directly to research into Pitt Hopkins Syndrome.
David Sweatt, PhD, Evelyn F. McKnight Chair, Dept of Neurobiology; Director, McKnight Brain Institute; University of Alabama at Birmingham
The identification of the dysfunctional TCF4 transcription factor gene as the genetic basis of Pitt-Hopkins Syndrome is a critical step forward in beginning to understand the diagnosis, etiology and molecular biology of PTHS. This project encompasses a set of studies to investigate the cognitive dysfunction associated with PTHS, focusing on mechanistic studies to understand the role of the TCF4 transcription factor in central nervous system function. For this project we are using genetically engineered mice in which the TCF4 gene has been manipulated in order to mimic human PTHS. This particular project is focused on investigating whether there is aberrant regulation of epigenetic molecular mechanisms, and altered transcriptional regulation of genes and small non-coding gene products in the PTHS model mice. For these studies we are particularly interested in learning and memory function as it relates to these molecular biological mechanisms in the CNS. Toward that end we are using next-generation high-throughput DNA sequencing methodologies coupled with epigenomics and bio-informatics approaches. Grant amount: $63,920.
Stephen J. Haggarty, PhD, Associate Professor of Neurology | Harvard Medical School and Massachusetts General Hospital
The additional funds will be used to further support a post-doctoral research scientist in the Haggarty laboratory who is developing assays with human patient specific, stem-cell derived neuronal to measure TCF4 expression at the mRNA and protein level. Additionally, methods for mapping TCF4 target genes using state-of-the-art techniques for chromatin immunoprecipitation coupled with high-throughput DNA sequencing (ChIP-seq) are being piloted. These studies are anticipated to provide important new insight into how the loss of TCF4 function may lead to changes in pathways important for neuroplasticity. Grant amount: $50,000.
Dr. David Sweatt, Department of Neurobiology, the University of Alabama at Birmingham
PTHS Foundation Funding Enables New Research Into the Neurobiological Basis of PTHS
With the help and financial support of the PTHS Foundation Dr. J. David Sweatt, Professor and Chairman of the Department of Neurobiology at the University of Alabama at Birmingham, has started a new project to investigate the molecular and neural basis of Pitt-Hopkins Syndrome (PTHS). Dr. Sweatt is a senior scientist in the field of learning and memory, with an track record of prior discovery related to intellectual disability.
The research in the Sweatt laboratory capitalizes on the recent discovery that PTHS is a neurodevelopmental disorder, the underlying genetic basis of which is mutation/deletion of the TCF4 gene. In PTHS patients the altered gene product is present throughout development but is also present in the fully developed CNS. PTHS is an orphan disease, and at present there is a profound lack of information concerning the molecular neurobiology underlying PTHS. Thus, the Sweatt laboratory will begin to investigate the molecular and cellular basis of nervous system dysfunction in PTHS, to lay a cornerstone of research that will allow the hope of the development of a treatment for these patients in the future.
In their study the Sweatt laboratory will undertake comprehensive behavioral testing of genetically engineered PTHS model mice (TCF4 heterozygous deficiency mice) focusing on learning and memory, and investigating whether there is altered function in the neurons of PTHS model mice. In addition the Sweatt lab will testing whether a specific category of drugs, histone deacetylase (HDAC) inhibitors, might ameliorate any behavioral and neurophysiologic deficits observed in the mice. The proposed studies will yield valuable information concerning the Intellectual Disabilities aspect of PTHS, and whether HDAC inhibitors might be a candidate treatment for this aspect of PTHS.
A gift of $85,000 was given to Dr. David Sweatt to begin this project by the PTHS Fund in June 2012.
Partnering with the Simons Foundation Autism Research Initiative
The PTHS research in the Sweatt laboratory is also being supported by a brand-new Simons Foundation Autism Research Initiative (SFARI) Explorer Award. In addition to manifesting intellectual disabilities, PTHS is an Autism Spectrum Disorder (ASD) and the autistic characteristics of PTHS are a crucial aspect of the syndrome. Thus, given their focus on autism the Simons Foundation has generously now begun funding research into PTHS. For their research project, in addition to studying the memory and neuronal characteristics of the PTHS model mice, the Sweatt laboratory will study the PTHS model mice in the domain of autistic behaviors as well. This important aspect of the research project will undertake behavioral studies to assess whether the TCF4 heterozygous deficiency mice manifest autistic-like behaviors, and also address whether HDAC inhibitors might ameliorate autism-like phenotypes in the mice. Studies of the PTHS model mice in terms of ASD-like behaviors are important not only because of their direct relevance to PTHS patients, but also because studies of the TCF4-deficient animals may give fundamental insights into the molecular neurobiology underlying the broader spectrum of autistic disorders. Furthermore, any potential drug treatments that ameliorate autism-like behaviors in PTHS mice might also be useful to consider for possible use with other ASD’s as well.
Additional grant funded in September 2012:
Dr. Sweatt’s group has just recently received a second grant to determine if TCF4 is necessary for normal cognitive function in a developed mature central nervous system. This work will lay the ground work for determining if PTHS is a developmental or chemical disorder in learning and memory or both.
Grant amount: $75,000, Fall 2012
Grant funded in September 2012:
The Chromosome 18 Clinical Research Center at the University of Texas San Antonio is partnering with Dr. Stephen Haggarty, at the Harvard Stem Cell Institute and Assistant Professor of Neurology at Harvard Medical School, to work on drug development. They will be using skin cells (fibroblasts) from individuals with Pitt Hopkins to create stem cells and then differentiate them into neurons (or other important cell types). They can then use these cell lines to screen a large variety of possible drugs relatively rapidly. This project is very significant, both for its importance for Pitt Hopkins and as a “proof of principle” that we can apply to other conditions involving the central nervous system.
In addition to his collaborative work with Dr. Cody at the University of Texas, San Antonio, Dr. Haggarty’s group is working on identifying common molecular pathways and networks dysregulated due to TCF4 haploinsufficiency, using specially developed isogenic PTHS stem cell models or neurons. This work will set the stage for the discovery of therapeutic targets aimed at improving cognition.
Grant amount: $85,000, Fall 2012
This grant was awarded to the University of Texas at San Antonio, with the Chromosome 18 Clinical Research Center, directed by Dr. Jannine Cody, in April 2012. One of the goals of this center is to be the international medical and educational resource for individuals with chromosome 18 abnormalities and their families. All families in the PTHS support group have the opportunity to enroll in this study. The Center interested in enrolling individuals with deletions as well as mutations.
Here are the goals and the plan summary of the grant, to be completed over the next three years, starting April 2012. The Pitt Hopkins Syndrome Fund will allocate money to the Chromosome 18 Clinical Research Center on a yearly basis. This center is also graciously contributing quite a large amount of funds (more than matching our grant amount) to complete this research study.
The objective of this research grant is to create an accurate description of the physical and behavioral consequences of an abnormality in the TCF4 gene. The ultimate goals are to provide:
· a physiological understanding of the phenotypes
· recommendations for specific therapies based on this understanding
We propose a stepwise process that maximizes both the likelihood of discovery and the use of funds. This process has been the basis of our other productive long-term projects on Chromosome 18. The specific steps are:
1. Biobank/ Primary Enrollment. This involves:
a. The collection of medical records on the affected individual and the provision of the medical records to us by the family
b. Having blood collected at the affected individual’s location and sent to us. We provide appropriate instructions and supplies for collection and shipping.
c. Extraction of DNA from the blood sample and the establishment of cell lines
2. Molecular analysis using a customized microarray that permits very fine resolution of the exact deletion on Chromosome 18
3. Comprehensive review and system-by-system abstraction of medical records on all affected individuals with 5 goals:
a. To create the most comprehensive syndrome description (i.e., as more patient records are reviewed, the common features, the range of features and the clustering of features, become increasingly clear)
b. To identify “missing information” (e.g., while the children are all developmentally delayed, we have no information about receptive language).
c. To delineate evaluations that might fill the information gaps, or to clarify ambiguities
d. To determine which of these evaluations can be done remotely (lower cost) and which require a comprehensive on-site evaluation.
e. To prioritize the various evaluations
4. Implement plan for on-site evaluation
To enroll in this research study sponsored by the Pitt Hopkins Syndrome Fund, please follow this link:
www.pediatrics.uthscsa.edu/centers/chromosome18 Be sure to list in your enrollment information that your child has a Pitt Hopkins Syndrome Diagnosis, and you are a part of the Pitt Hopkins Syndrome Support Group. If you would like, please write the support group to let us know you have enrolled in the study.
For this grant, Dr. Cody budgeted: $5,719 for the first year (given in April 2012 by the PTHS Fund), $21,225 for the second year, and $8,006 for the third year. This comes to a total of $34,950 for the three years. The PTHS Fund will send allocated money on a yearly basis.