The Pitt Hopkins Research Foundation is committed to directly funding the most promising research available in the world to help find a treatment and ultimately a cure for Pitt Hopkins syndrome.

We started The Pitt Hopkins Research Foundation with the singular goal of treating and ultimately curing Pitt Hopkins in people. Since our beginning in 2012, we have funded over $2,000,000 in research grants to scientists who have created Pitt Hopkins Mouse models and neuronal stems cells. They use these models to see what drugs may help ameliorate symptoms. In just 6 short years, scientists discovered not one, but two therapeutics that have reversed the symptoms of Pitt Hopkins in the mice. We are working hard to bring these drugs to trial THIS YEAR. 

This research has far reaching effects into the science of memory and learning. Because we already KNOW the gene that causes PTHS- TCF4, we are in an important place to fund meaningful research, research that could possibly give insight to other learning, memory and motor disorders with no known cause like Alzheimers, Autism, Epilepsy and Parkinsons. 

Mind Map of the Pitt Hopkins Research Foundation’s Road to Treatment:


PTHS Late Onset Gene Therapy Grant

Ben Philpot, PhD, UNC-CH, and Steve Gray, PhD,  UT Southwestern, $123,970, first installment, $91,740 second installment, 2018.

Our labs are currently developing and testing adeno-associated virus (AAV) vectors expressing human TCF4 isoforms (hTCF4) to determine whether early postnatal introduction of TCF4 can normalize phenotypes in Pitt-Hopkins syndrome (PTHS) model mice. Our preliminary data indicate that AAV9/hTCF4(B-) vectors are well tolerated when delivered at the highest concentration to neonates. Encouraged by our preliminary findings suggesting safety of the viral vectors, we will now determine the extent to which adult-onset gene therapy can correct PTHS phenotypes. Further, we will test additional isoforms of TCF4 to evaluate if hTCF4(B-) is the best candidate for gene therapy. These experiments will complement ongoing experiments in which we are optimizing protocols and testing for recovery with neonatal gene therapy. 


Epigenetic Therapy to Treat Pitt-Hopkins Syndrome (PTHS)

Andrew J. Kennedy, PhD, Department of Chemistry and Biochemistry, Neuroscience Program, Bates College, Million Dollar Bike Ride Pilot Grant (UPenn), $49,263.00, 2017-2018.

We aim to use a mouse model to test the hypothesis that an epigenetic therapy can be effective in treating cognitive deficits associated with PTHS.


Pilot study to identify small molecule activators of TCF4 as a treatment for Pitt-Hopkins syndrome

PI: Philpot, Benjamin D., PhD., University of North Carolina at Chapel Hill. Million Dollar Bike Ride Pilot Grant (UPenn), $49,263.00, 2017-2018.

Pitt-Hopkins syndrome (PTHS) is a complex neurodevelopmental disorder caused by insufficiency of the transcription factor 4 (TCF4). The reduced TCF4 expression is caused by a mutation in one of the two gene copies of TCF4.  However, the other TCF4 gene copy remains functional.  As one potential treatment for PTHS, we are trying to pharmacologically upregulate the levels of the intact copy of TCF4. To this end, we are using a high throughput drug screen to find small molecules that increase the activity of the intact TCF4 gene.   The TCF4 activators that we identify have the potential to treat PTHS by rebalancing TCF4 activity.


The Sarah Huffman Award for Promising Young Researchers:

Novel Therapeutics for Pitt Hopkins Syndrome

Annah Moore, Graduate Student, Pharmacology Department Vanderbilt University, under the Mentorship of: Dr. David Sweatt, Chairman, Department of Pharmacology and Dr. Colleen Niswender, Research Associate Professor of Pharmacology, $62,000, 2017-2018

This project is focused on the discovery of small molecules designed by the Vanderbilt Center for Neuroscience Drug Discovery as potential therapeutics for Pitt Hopkins Syndrome (PTHS). Preliminary experiments have shown cognitive enhancing properties in Pitt Hopkins model mice after treatment with a drug that acts at the M4 muscarinic acetylcholine receptor. This compound will be tested in additional mouse models for PTHS and additional candidate drugs will also be investigated. Abnormal breathing has been documented in a PTHS mouse line, and further characterization this trait is planned.


Single concentration re-purposing screen of 1280 library compounds on human KCNQ1 and Nav1.8 channels

Aaron Gerlach, Ph.D, Icagen Inc., and Sean Ekins, PhDIon Channel Inhibition Grant, $35K, 2017
Starting the deeper dive of Five top compounds from Initial screen. Larger drug repurposing proposal in review.  

Aim of study: The aim of the study is to test the inhibitor activity of the 1280 compound Prestwick library against recombinantly expressed human KCNQ1 and Nav1.8 channels.


A model of Pitt-Hopkins Syndrome, and efficacy testing of HDAC inhibitors at The Jackson Laboratory 

Jackson Lab, HDACi:  Vorinostat Control and Other HDACis, First installment: $27,117, 2017

Validation of behavioral testing in B6;129-Tcf4tm1Zhu/J mice.


Protein Replacement Therapy Grant

Michelina Iacovino, PhD Assistant Professor, UCLA, protein replacement therapy,  $50K, 2017-2018

Timeline and milestones 

  • Plasmid preparation: TCF4 reporter and TCF4 overexpressing construct about 4-6 months. 
  • iPS cells generation (including breeding time for TCF4 mice) 3 month (this process will overlap
    with Plasmid preparation). 
  • Cell type system for TCF4 overexpression and TCF4 uptake 1-2 months and will follow plasmid
  • Uptake assay and TCF4 protein purification 2-4 month following Cell preparation.


Drug Validation Initiative 

Patricia Cogram, PhD, Project coordinator (PI, Science Faculty, University of Chile). Collaborator: Dr. Robert Deacon, (Experimental Psychology Department, Oxford University, UK) 
Compound testing in mice, $25K, Drug Validation Initiative, Pre-clinical studies for five pharmacological compounds, 2017-2018

Different pharmacological compounds will be tested using the Pitt Hopkins Syndrome (PTHS) mouse model to assess their impact on neuronal migration, establishment of connectivity, synaptic function and behavior. Measurements will be carried out at different levels, ranging from single cells to behavioral studies to explore the mechanisms of drug effect in PTHS. 


A drug repurposing project to identify potential drug candidates for the treatment of Pitt Hopkins Syndrome

Timm Guillams, PhD, Healx, Cambridge, UK, $45,000, 2017-2018

Phase 1: Bicuration: A biocuration phase precedes the full drug repurposing work to provide a comprehensive data analysis and landscape of PHTS and its current treatment options. This first step is essential to ensure drug repurposing predictions with a higher likelihood of success.

Phase II: Drug Repurposing & Healx Methods, Drug-Gene Expression Matching, Prediction of Repurposed Indications with Similarity Matrices, Similarity Network Analysis based upon Predicted Protein Targets, Literature Mining, Drug Ranking

Phase III: Expert Pharmacology Review


Ann D. Bornstein Gene Therapy Grant:

PTHS Gene Therapy Grant

Steve Gray, PhD, Principal Investigator, and Ben Philpot, PhD, Co-Principal Investigator, University of North Carolina at Chapel Hill, $68,156, 2016-2017

The laboratories of Dr. Ben Philpot and Dr. Steven Gray at the University of North Carolina at Chapel Hill are collaborating on a project to investigate the feasibility of a gene therapy approach for Pitt-Hopkins syndrome (PTHS). This collaborative study combines Dr. Philpot’s expertise in autism and neuroscience with Dr. Gray’s expertise in translational gene therapy for neurological disorders. The project will follow a platform gene transfer approach using AAV vectors taken by Dr. Gray to initiate a human Phase I trial for Giant Axonal Neuropathy. The approach uses an engineered virus, AAV, to carry a functional copy of the gene disrupted in PTHS into the body and distribute it across the nervous system. In this fashion, a single dose of this gene therapy could permanently restore the gene to cells across the nervous system, treating the disease at its source. This initial pilot study is meant to assess the potential of this as a treatment approach for PTHS, and identify any roadblocks that may exist.


Pharmacological rescue and screening in a Pitt Hopkins model

Daniel R. Marenda Ph.D., Principal Investigator, Drexel University, Awarded $50,000, UPenn, MDBR, 2017

Screening drugs in cells and animals is essential to identifying therapeutic compounds and targets for disease. Though screening drugs in cells is fast, these drugs often fail when tested in animal models of a disease. However, screening in animal models (such as mice and rats) is far too expensive and time consuming to make large scale drug screening feasible in most cases. This proposal will utilize a novel animal model for Pitt Hopkins by using the fruit fly Drosophila melanogaster to screen for potential therapeutic compounds for the treatment of this disorder. Drosophila offer a powerful, well tested, cheap, and quick way to test for new drugs in an established animal model.

Using an established Drosophila model for Pitt Hopkins, we performed a small drug screen and identified three drugs that have been previously identified as having potential for therapeutic use in Pitt Hopkins, suggesting that this model is capable of identifying molecules with the potential for further exploration. We are expanding upon this approach, and will use this animal model to screen for additional compounds in a large library of drugs. Our hope is to identify new compounds in this animal model which can be further explored in mammalian models of Pitt Hopkins, and eventually be furthered explored in humans.


Identification of direct target genes of TCF4 in neurons

Tonis Timmusk, PhD, Principal Investigator, Mari Sepp, PhD, Co-Principal Investigator, Tallinn University of Technology, Estonia, Awarded $50,000 UPenn, MDBR, 2017

Pitt Hopkins syndrome (PTHS) is a genetic developmental disorder that severely affects cognitive, motor and social development. PTHS is charachterized by distinct facial features, absent speech, absent or delayed walking, low muscle tone, gastrointestinal problems and autistic-like behaviour. The patients may develop breathing problems and/or epilepsy. PTHS has been diagnosed in less than 1000 people in the world. It is caused by mutations in one of the two alleles of a gene called TCF4.  Most of the mutations found in PTHS patients are of de novo origin meaning that the mutation is not present in the parents. TCF4 gene has attracted wider interest mainly due to the fact that polymorphisms (genetic variations that may create predisposition to a disease) in this gene have been linked to schizophrenia.

TCF4 gene encodes a protein named Transcription Factor 4 (alias ITF2, SEF2 or E2-2). Transcription factors are proteins that regulate expression of genes. There are about 2000 different transcription factors encoded by the human genome. TCF4 is broadly expressed and involved in the development and functioning of many different tissues and cell types.  Evidence is accumulating that in the nervous system TCF4 plays an important role in proliferation, differentiation and migration of neurons, as well as brain plasticity – a process that enables the brain to rewire itself in response to the stimuli from learning and experience.

The goal of the current project is to identify genes that are regulated by TCF4 in the brain neurons. We will generate adeno-associated virus based vectors for overexpression and knockdown of TCF4 protein, identify TCF4-regulated genes and determine the binding sites of TCF4 in its target genes. The knowledge of TCF4 target genes is instrumental in deciphering the role of TCF4 in biological processes that contribute to the pathology of Pitt Hopkins syndrome. It also allows us to test whether increasing the activity of the remaining TCF4 protein (produced from the intact allele in PTHS patients) by pharmacological modulation is feasible for PTHS treatment. Focusing on target genes that are related to brain plasticity, a process that is ongoing lifelong, enables us to obtain insights into adult functions of TCF4 that in turn may represent suitable targets for therapeutic intervention of Pitt-Hopkins syndrome.


Characterization and Generation of PTHS Model Mice for Rational Therapeutic Discovery

Benjamin D. Philpot, Ph.D., Principal Investigator; Alexander D. Kloth, Ph.D., Co-Principal Investigator; Courtney L. Thaxton, Ph.D., Co-Principal Investigator, The University of North Carolina at Chapel Hill, Awarded $75,000, 2016

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder characterized by intellectual disability, absent speech, seizures, ataxia, and breathing anomalies. In support for future therapeutic development for PTHS, we will pursue two independent aims: (1) to uncover the neural impairments that are common across multiple PTHS mouse models, and (2) to develop new tools to analyze TCF4 expression in neuronal subtypes throughout development and adulthood. In the first aim, we will follow up on our finding that long-term changes in synaptic function related to experience are enhanced in multiple PTHS-related mouse models. We hypothesize that this deficit is related to altered function of a glutamate receptor, the NMDA receptor, and we will rigorously test this hypothesis using electrophysiology, biochemistry and pharmacological methods in multiple PTHS-related mouse models. In the second aim, we will develop a unique mouse model toward determining effective drug targets that affect TCF4 expression levels, as well as be able to alter TCF4 activity in a spatiotemporal manner. This novel binary “reporter-reinstatement” mouse will not only allow for a stream-lined and genetically precise approach to drug discovery for PTHS, but also will allow us to determine the most efficacious time in which to reinstate TCF4 function to alleviate the pathophysiologies associated with PTHS. In all, the proposed project pursues incisive approaches that will provide guidance to the development of PTHS therapeutics.


Kindal Kivisto Award for Promising Young Researchers:

Investigating Therapies for Pitt-Hopkins Syndrome

Andrew John Kennedy, Ph.D., Principal Investigator, Bates College; J. David Sweatt, Ph.D., Co-Principal Investigator, Vanderbilt University, Awarded $75,000, 2016

The central strategy of our research program consists of two goals: the near-term goal to identify FDA approved drugs as potential translatable therapies for Pitt-Hopkins Syndrome (PTHS) and the long-term goal to develop novel neuroepigenetic therapies that fundamentally reverse the effects of PTHS. Over the past three years, we have characterized a genetically engineered heterozygous deletion mouse model of PTHS (Tcf4 +/-), validated the histone deacetylase enzyme Hdac2 as a target to treat the cognitive deficits associated with PTHS, and undertaken a drug screening program. This grant will investigate the efficacy of Fingolimod (trade name Gilenya), as well as other FDA approved therapeutics that target Hdac2, to improve learning, problem solving, and associative memory in PTHS mice. These experiments will focus on identifying a plausible drug candidate that can be translated to a clinical setting and effectively improve cognition in PTHS patients. Additionally, more advanced epigenetic therapies will be developed to address the genetic cause of PTHS. Every person has two functioning copies of Tcf4 with the exception of individuals with PTHS, who have a mutation or deletion that yields only one functioning copy. Epigenetic therapies, which alter the epigenetic states at specific genes within the genome, are being designed to allow PTHS models to use their one functioning copy of Tcf4 twice as much, hopefully restoring full Tcf4 function and reversing the cognitive deficits associated with Pitt-Hopkins. Taken together, these approaches investigate already-available FDA approved drugs and cutting edge genetic techniques to identify potential therapies that improve cognition in the near-term and attempt to address and compensate for the underlying cause of Pitt-Hopkins Syndrome.


Exploring the impact of a TCF4 mutation on the physiology of inhibitory neurons of the prefrontal cortex

Brady Maher, Ph.D., Principal Investigator; Huei-Ying Chen Ph.D.; Stephanie Cerceo-Page, Ph.D.; Lieber Institute for Brain Development, Johns Hopkins School of Medicine, Awarded $50,000, UPenn, MDBR, 2016

PTHS is a neurodevelopmental disorder due to mutation or deletion of one copy of the TCF4 gene. TCF4 is a transcription factor that can regulate the expression of many downstream genes and therefore regulates the genetic programs necessary for normal brain development. We measured the expression of TCF4 mRNA across the lifespan in humans and rodents and observed a peak in TCF4 expression occurs during the formation of the cerebral cortex, a region of the brain important to higher cognitive functions including learning and memory. Using a mouse model of PTHS that has a mutation in one copy of the TCF4 gene, we observed that TCF expression is blunted during the developmental peak in expression compared to control animals, and we believe this indicates a causal time period for the development of PTHS. Unfortunately, this critical period occurs in utero and prior to when diagnosis is currently made, thus complicating our ability design treatment strategies during this causal phase of the disorder. Therefore, our research group is focused on understanding the underlying pathophysiology that produces symptomatology in PTHS so that we can normalize this pathophysiology in children and adults. Using our animal models of PTHS, we have identified a sodium channel that is normally expressed in the peripheral nervous system, but is ectopically expressed in the central nervous system when TCF4 is mutated. Experiments are currently underway to determine if blocking this Na channel with drugs can lead to improvement on behavioral tests in our PTHS mouse model. In our current proposal, we would like to follow up a preliminary result that suggests inhibitory transmission onto excitatory neurons in the cortex is decreased in the PTHS mouse compared to control littermates. In addition, using RNA sequencing of the PTHS mouse model we observed that many genes that are specific to inhibitory neurons show decreased expression compared to control animals, and we identified a specific population of inhibitory neurons (cortistatin positive) that normally show high levels of TCF4 expression. These cortistatin positive interneurons are known to release a neuropeptide called cortistatin that has been shown to inhibit the generation of seizures and regulate sleep states. Given the prevalence of seizures and sleep disturbances in PTHS, we believe this population of inhibitory neurons may underlie clinical aspects of the disorder. Therefore, we propose to breed the PTHS mouse with another mouse that allows us to visualize cortistatin positive interneurons and we will use electrophysiology and microscopic imaging to determine if these cells are disrupted in the PTHS mouse model compared to control littermates. If deficits are observed in this population we will determine the cellular and molecular mechanism using pharmacological rescue and/or molecular phenocopy. Identified molecular mechanisms will then be deemed potential therapeutic targets and these targets will be tested for their ability to normalization of behavioral deficits in the PTHS mouse.