Pitt Hopkins Research Foundation appoints new board members, 12/5/16

FOR IMMEDIATE RELEASE

Media contact: Jessica Fletcher, Director of Communications, information@pitthopkins.org

Pitt Hopkins Research Foundation appoints new board members;
recognizing a continued commitment to fundraising and research

Los Angeles, Calif. (December 5, 2016) – Effective January 1, 2017, the Pitt Hopkins Research Foundation (PHRF) is proud to announce the appointment of three newly-elected advocates of the Pitt Hopkins Syndrome community to serve on the Foundation’s Board of Directors: Nicole Almond Anderson, MNLM (Phoenix, Ariz.); Corinne DePersis, Ph.D. (Denver, Colo.) and Will Eyres (New Brunswick, Canada).

The mission of the Pitt Hopkins Research Foundation is to support research dedicated to finding a treatment, and an eventual cure of Pitt Hopkins syndrome and other similar disorders. The PHRF is served by two boards; the Board of Directors, comprised of parents and professionals who volunteer their time, so that nearly 100% of all funds donated go to finding a cure, and the Scientific Advisory Board. Together, these individuals promote awareness of Pitt Hopkins Syndrome, dedicate their time to advancing research andbringing practical treatment into current medical practice, as well as support families of children and adults with Pitt Hopkins Syndrome.

“Each one of these individuals shown an incredible dedication to helping not only their own kids, but all kids with Pitt Hopkins and we feel incredibly lucky to have them join the team,” said Audrey Davidow, President of the Board of Directors for the Pitt Hopkins Research Foundation.

Anderson, DePersis and Eyres join current board officers and general members: Audrey Davidow Lapidus, President, Theresa Pauca, Vice President; Heather Maginn, Secretary; Diane Sellew, Treasurer; Jessica Fletcher, Director of Communications; Eric Lapidus, Director of Fundraising; Paul Pauca; Jack Maginn; Jeff Davidow; Diane Krell; Traci Green and Claudette Mirigliani.

Learn more about the newest board members below.

Nicole Almond Anderson, Mother to Alexandra, 22 mos. old

“Seven months ago Alexandra was diagnosed with Pitt Hopkins Syndrome and in an instant the dreams I had envisioned for her were crushed. As much as I grieved this news, I also vowed to never stop fighting for a better life for our daughter,” said Nicole Almond Anderson. “Just hours after getting the call from the neurologist, I found the Pitt Hopkins Research Foundation and was immediately welcomed into their courageous community by their president, Audrey. I remember telling her that night how ready I was to start fundraising for a cure. From that conversation (and from an immense fire burning within me), we launched Alexandra’s Pitt Crew to garner support from friends and family. Only 90 days after publicly announcing the news and beginning our fundraising campaign, we now have 175 active donors that have given nearly $20,000 to fund a cure. We are so incredibly grateful for their support,” she added.

Anderson believes her experience, education and dedication has equipped her with the essential skills needed to be a change-agent for her daughter and the greater Pitt Hopkins community. For nearly a decade, Anderson’s career at Arizona State University (ASU) has provided her with experience in nonprofit event planning, donor engagement and marketing and communications. Currently, she is the Manager of Marketing, Communications and Stakeholder Relations for the ASU Lodestar Center for Philanthropy and Nonprofit Innovation. Before coming to ASU, she was at the Health Industry Business Communications Council, a nonprofit that helps to ensure safe and efficient healthcare delivery via electronic communication devices. Anderson received a BA in Journalism and Mass Communication from the Walter Cronkite School of Journalism and Mass Communication at ASU, as well as Masters of Nonprofit Leadership and Management from the College of Public Service & Community Solutions at ASU. She also serves as President of the Sun Devil Club’s Young Professionals Group and previously she was the Vice President of the ASU Young Alumni Chapter, a member of the Young Nonprofit Professionals Network and a Class 36 member of Valley Leadership. She now looks forward to combining her passion to serve, along with advocating for those that are developmentally disabled, by getting involved in local pediatric disease advocacy groups.

“As devastating as getting the diagnosis was, we also were filled with hope after reading about the incredible research already being funded by the PHRF. I am beyond humbled and honored to join their board and I can say with certainty that Alexandra’s incredible Pitt Crew and her family and I look forward to making a positive impact on the organization and helping to continue this critical work,” she concluded.

Corinne DePersis, Mother to Madeleine, 2 years old

“When we received the call that Madeleine had been diagnosed with Pitt Hopkins Syndrome, my world shattered. We had been fighting for months and months to help Maddie ‘catch back up’ to the developmental milestones that kept passing us by. For a fleeting moment, the diagnosis felt like all that fighting was for naught, and her diagnosis predetermined her fate. But that night, with swollen, tear-filled eyes, I found the Pitt Hopkins Research Foundation and the members who had picked up the fight against this devastating genetic condition,” said Corinne DePersis, Ph.D. “Every parent wants to do everything they can for their children, to provide every opportunity to succeed which is why I felt so strongly about becoming a member of this board. I am dedicated to expanding the breadth and depth of research to help discover treatments and ultimately a cure for Pitt Hopkins Syndrome. I am so grateful for the relationships with the scientific community the foundation has already cultivated and I look forward to enriching these relationships,” she added.

DePersis’ background has also uniquely prepared her for the Pitt Hopkins Research Foundation board of directors. She received her Bachelors of Science degree in Biology from the State University of New York College at Geneseo. After which she received a Cancer Research Training Award for a year of research at the National Cancer Institute at the National Institutes of Health main campus in Bethesda, Md. DePersis then continued her scientific career by accepting a graduate student position at the University of Colorado Health Sciences Campus in Denver, Colo. where she studied Immunology, culminating in her Doctoral degree. When her daughter, Madeleine, started showing concerning symptoms, DePersis left her professional life to be a full-time Mom and manager of Madeleine’s health and therapy regimen.

“My formal scientific training provides me with the keen understanding of the challenges we face in research. I also understand the enormity of the financial burden required to fund research projects we need to advance the science towards a real breakthrough,” said Corinne DePersis, Ph.D. She has shown a strong commitment to fundraising and has hosted several successful fundraisers including ‘Madeleine’s 2nd Birthday Party’ which raised over $5,000 and the ‘Pitt Hopkins Awareness Day event’ in Denver which yielded several thousand more. “It is time to explore more substantial funding sources and I look forward to new opportunities doing such as part of the board,” she added.

Will Eyres, Father to Iris

“I am honored to be part of the Pitt Hopkins Research Foundation, an amazing organization that has accomplished so much in its short history, and look forward to contributing to the ultimate goal of finding a cure for all our kids,” said Will Eyres.

Eyres has worked around the world in the maritime industry for ten years and currently he and his family reside in New Brunswick, Canada. “Fundraising is one of the best things we can do for our kids and we are very fortunate to have the full support of our entire family,” he added.

“‘Rafa’s for Research’ has been a great event and we hope to make it better every year and find additional avenues of fundraising in the near future,” he added. Rafa’s Cafe raised an astounding $32,000 for research on November 5, 2016, during the Dallas Family Conference. Additional thanks to Raphael and Kathy Carreon, owners of Rafa’s, and the grandparents of Iris Eyres, who was diagnosed with PTHS last year.

For additional information regarding the Pitt Hopkins Research Foundation, visit https://pitthopkins.org. If you have questions, please email information@pitthopkins.org.

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ABOUT THE PITT HOPKINS RESEARCH FOUNDATION

Established in 2013 as a 501(c)3, the Pitt Hopkins Research Foundation (PHRF) exists to support critical research dedicated to finding a treatment, and an eventual cure of Pitt Hopkins syndrome and other similar disorders. Pitt Hopkins Syndrome (PTHS) is a rare, neuro-developmental disorder caused by a mutation/deletion of the TCF4 gene on the 18th chromosome. It is characterized by significant developmental delays, problems with motor coordination, breathing abnormalities and seizures. Most individuals with Pitt Hopkins do not develop functional speech. Pitt Hopkins affects all races and both genders equally. Since the gene that causes Pitt Hopkins was only found in 2007, currently there are approximately 650+ people in the world diagnosed with this incredibly rare syndrome. The Pitt Hopkins Research Foundation is dedicated to supporting the Pitt Hopkins community with resource recommendations, scientific symposiums and family conferences, parental support and the latest medical information. For more information, please visit: https://pitthopkins.org.

PDF File:  new-board-members_press-release_phrf_dec-2016_final

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Madeleine’s Endless Sunshine

Madeleine Amelia DePersis Zarlengo has not only a big name, but a big burden to carry. She has Pitt Hopkins Syndrome. Despite her diagnosis, she is so light, effortless in her ability to bring joy to all and a provider of endless sunshine. It seemed only fitting that in honor of her second birthday, August 3, she have a “Sunshine” themed party to raise awareness and funds for the Pitt Hopkins Research Foundation.

Threat of rain didn’t scare away guests who were all rewarded with perfect weather just as the party began. One hundred of her closest friends and relatives joined together in her backyard to celebrate all of her accomplishments over the past two years. Madeleine had a lot to celebrate! She had just become independently mobile as an official “crawler.” Standing was rapidly becoming a favorite pass time and attending school was a whole new adventure just starting.

Guests enjoyed the afternoon sipping on “Liquid Sunshine” (a pineapple and tequila cocktail) and sparkling pink lemonade. No one went hungry either with plenty of Madeleine’s Dad’s famous smoked pulled pork, Madeleine’s Grandmother’s inspired Mac ‘n Cheese and Madeleine’s favorite smokey bacon baked beans. Dessert satisfied everyone’s sweet tooth with many options including pink-chocolate dipped rice crispy treat pops, Madeleine’s Mom’s signature pineapple upside-down mini cupcakes and a two-tier strawberry lemonade birthday cake.

Never a dull moment, there was lots to do besides just eat! Thomas and Paker, Maddie’s friends and brothers to Henry, another little boy with Pitt Hopkins Syndrome, performed street magic and created balloon animals. Friends enjoyed splashing around in the water table and cooling down in the wading pool. The biggest hit, and possibly the most simple, were the endless supply of bubbles from the bubble machine that filled the yard with delight.

In lieu of gifts, Madeleine’s Mom and Dad requested donations be made to the Pitt Hopkins Research Foundation. There could be no better gift than a contribution to the scientific research seeking treatments and a cure for the rare syndrome that affects Maddie every minute of every day. Almost $5000 was collected in Madeleine’s honor that afternoon.

 

To say thanks, every child received a personalized gift bag with sunglasses and other goodies and every guest was sent home with sunshine shortbread cookies. But the smile on Madeleine’s face when she smashed her cake and then splashed in the pool was all anyone at that party needed to know how grateful she was for their support.

Madeline’s family has gone onto raise another 3K for Pitt Hopkins Awareness Day on September 18th, 2016, in honor of their sweet sunshine.  

 

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Press Release, 4th Annual Pitt Hopkins Syndrome Day 9/18/16

FOR IMMEDIATE RELEASE
PITT HOPKINS:

The Pitt Hopkins Research Foundation celebrates its fourth International Pitt Hopkins Syndrome (PTHS) Day to Raise Awareness and Funding for Pitt Hopkins Research

Los Angeles, California September 6, 2016 –The Pitt Hopkins Research Foundation (PHRF) is proud to announce the celebration of its fourth annual International Day of Recognition for Pitt Hopkins Syndrome, a rare neurodevelopmental disorder caused by a spontaneous mutation on the 18th chromosome.

To bring further awareness to the 18th chromosome, we have chosen the 18th of September as our annual awareness day. Families and friends around the globe will celebrate children affected by Pitt Hopkins Syndrome and begin to expand recognition for the disorder and help raise awareness and funding for research towards a cure.

GOALS FOR AWARENESS DAY

On Sept. 18th, as we celebrate our children and all they have achieved we want to take the opportunity to introduce more people to the beauty and trials of living with Pitt Hopkins.

  • We want to promote our reasons for research, our belief and dedication to finding a cure (see below) and encourage people to donate to our foundation.
  • We want medical professionals, in particular pediatricians, to learn more about the symptoms and features (see below) so that they can refer their patients for genetic testing in a timely manner.
  • We want families with undiagnosed, developmentally delayed children to perhaps see in the faces of our children, something familiar. We want them to know there is new testing available–Whole Exome Sequencing –that just might be able to help them find the answers they’ve been searching for.
  • We want other professionals that work with children and their families with special needs, eg kindergarten teachers, special needs teachers, OTs , physiotherapists to know the symptoms and features.
  • We want any families who have been diagnosed to find our support group at www.pitthopkins.org and join us!

WHAT IS PITT HOPKINS SYNDROME?

Pitt Hopkins is a severe neurological disorder caused by loss of function of the TCF4 transcription factor located on chromosome 18. PTHS is characterized by developmental delays, breathing problems of episodic hyperventilation and/or breath-holding while awake (55%-60%), recurrent seizures/epilepsy (40%-50%), gastrointestinal issues, and distinctive facial features. Most do not develop speech. Not all of these symptoms need to be present to warrant genetic testing.

PTHS was first described by D. Pitt and I. Hopkins in the Australian Pediatric Journal in 1978. The connection to TCF4 was not established until 2007 when it was found to play an essential role in the development of the nervous system and the brain. Any functional deficiency of TCF4 greatly affects how a child develops over time.

Currently about 650 people have been diagnosed with Pitt Hopkins. However, given the recent discovery of the gene in 2007, there are likely many more out there who remain undiagnosed. Overall prevalence of PTHS is unknown. However, one laboratory estimated that the frequency of chromosome 18q21 deletions associated with PTHS is between 1 in 34,000 and 1 in 41,000. An estimate from another researcher is 1 in 200,000-300,000. Researchers will need to recognize individuals with PTHS in all age groups first and molecular analyses should be more widely available too, before this estimate is more accurate. PTHS occurs in both males and females and is not limited to a specific ethnic background.

WHY WE BELIEVE IN A CURE

In the past, genetic syndromes like Pitt Hopkins and Down Syndrome, for instance, were thought to be incurable. But that tide is turning. In 2010, Tom Insel, Director of the National Institute for Mental Health said, “Just three years ago, I would have said that [intellectual disability] is a disability needing rehab, not a disorder needing medication. But it’s all changing.”

Right now, there are clinical trials for similar neurodevelopmental disorders like Rett Syndrome and Angelman Syndrome using compounds that have reversed the syndromes in mice. This has just happened in the last five years, and gives us a great deal of hope that a reversal, or at least amelioration of Pitt Hopkins symptoms, could be possible in humans, too.

We started The Pitt Hopkins Research Foundation with the singular goal of reversing Pitt Hopkins in people. In the last four years we have funded nearly $2,000,000 in research grants. Scientists at University of Alabama and University of North Carolina have created Pitt Hopkins Mouse models and neuronal stems cells and are testing them to see what drugs may help ameliorate symptoms. And this year, scientists discovered not one, but two therapeutics that have reversed the symptoms of Pitt Hopkins in the mice. We hope to bring these drugs to trial in 2017.

Although there are only 650 diagnosed, 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.

ABOUT THE PITT HOPKINS RESEARCH FOUNDATION

The Pitt Hopkins Research Foundation is an all-volunteer organization of families and professionals dedicated to finding a cure for Pitt Hopkins through the funding of an aggressive research agenda, education, and advocacy. Our goal is to bring practical treatment into current medical practice as quickly as possible. In just four years the PHRF will have raised and distributed nearly $2,000,000 in grants and fellowships.

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Gene Therapy Grant Awarded, Drs. Steve Gray & Ben Philpot, UNC-CH

Gene therapy success stories are not only a hope but now becoming a reality. We won’t let Pitt Hopkins fall behind in this exciting and promising research. In August of 2016 the Pitt Hopkins Research Foundation awarded its first gene therapy grant, to Dr. Steve Gray at UNC and one of our pioneer heroes and researchers Dr. Ben Philpot. Here’s to Pitt Hopkins heroes old and new… And to the promise of gene therapy!

Grant summary

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.

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Alexandra’s Pitt Crew

Every parent that has been on the receiving end of a diagnosis can relate to this. Alexandra is a sweet, beautiful 18 month old little girl who was recently diagnosed with Pitt Hopkins syndrome. Her mom and dad put together this beautiful video capturing their journey. Please take a few minutes to watch. Thank you Nicole and Matt Anderson, for putting into words what so many of us have felt in that moment of diagnosis and the worry of the unknown future for our kids. We are all in this together.

To follow along Alexandra’s journey, visit alexandraspittcrew.org and on Facebook at Alexandra’s Pitt Crew.

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HDACi meds may reverse effects of Pitt Hopkins, Drs. Kennedy & Sweatt

Dr. Andrew Kennedy and Dr. David Sweatt publish findings that show HDACi meds may reverse effects of Pitt Hopkins

The very first grant the Pitt Hopkins Research Foundation made back in 2012 was to the lab of Dr. David Sweatt at the University of Alabama Birmingham. He needed the money to hire the most promising young researcher he could find to devote his career to Pitt Hopkins. He found that in Dr. Andrew Kennedy. They are both scientists with hearts as big as their brains, and the more we learn about science, the more we know how incredibly lucky we are to have them both in our court. Dr. Kennedy just started his career as a professor at Bates College in Maine. Dr. Sweatt is now the chair of the pharmacology Department at Vanderbilt University. This paper is the culmination of their incredible work at UAB… and shows a very promising treatment for Pitt Hopkins. So what does that mean? It means there is an already FDA approved medicine reversing the symptoms of Pitt Hopkins in mice. It means there is increasing evidence we will be able to reverse symptoms in our children. It means we are actively pursing clinical trials. And it means, more than anything, that we will continue to fight for every little miracle.

Thank you Drs. Kennedy, Sweatt and UAB for doing this amazing work… and to all those who supported it, we cannot EVER thank you enough!

Read full article here:  http://www.cell.com/cell…/fulltext/S2211-1247(16)31036-1

 

Study suggests new way to treat rare autism disorder

by Bill Synder | Thursday, Aug. 25, 2016, 11:01 AM

A protein that plays a powerful role in learning and memory may be a key to improving treatment of a rare autism spectrum disorder called Pitt-Hopkins syndrome (PTHS), a new study suggests.

J. David Sweatt, Ph.D., the new chair of the Department of Pharmacology in the Vanderbilt University School of Medicine, has been studying the protein, called transcription factor 4 or Tcf4, for several years.

In a paper published this week by the journal Cell Reports, Sweatt and his colleagues at the University of Alabama at Birmingham (UAB) report that mice deficient in Tcf4 exhibit impairments in social interaction, vocalization, learning and memory characteristic of PTHS.

The impairments were “normalized” when the mice were given small-molecule drugs called HDAC inhibitors, which alter Tcf4-associated gene expression in the brain. The finding suggests that “broadly acting, epigenetically targeted therapeutics … might be particularly beneficial in PTHS patients,” the researchers concluded.

“We are quite excited by these findings, said Sweatt, a Vanderbilt University-trained pharmacologist who formerly chaired the Department of Neurobiology and directed the McKnight Brain Institute, both at UAB.

“Pitt-Hopkins Syndrome is an orphan disease that has not been extensively studied,” he said. “Having identified one potential avenue for possible therapeutics is an important step forward.”

Epigenetics refers to environmental factors that affect DNA transcription, the read-out of the genetic code, and thus gene expression. For example, histone deacetylase (HDAC) enzymes help regulate the way DNA is packaged and transcribed in part through acetylation, by adding acetyl groups to the histone proteins that coordinate gene structure.

Transcription factors like Tcf4 adjust the transmission of signals across the synapses, or gaps between nerve cells, a phenomenon known as synaptic plasticity. A type of synaptic plasticity called long-term potentiation, or LTP, is associated with the brain’s ability to learn, acquire language and lay down memory.

It’s been known for some time that Tcf4 exerts its effects on transcription by attracting HDACs. Drugs called HDAC inhibitors have been long used in psychiatry and neurology to stabilize mood and prevent epileptic seizures. More recently they have been studied as possible treatments for cancer, Alzheimer’s disease and depression.

Through their mouse model, Sweatt and his colleagues connected the observed effects of Tcf4 and HDACs on gene expression in the brain. Their study adds credence to the notion that chemical modification of DNA and DNA packaging can result in to long-lasting behavioral change, even post-developmentally.

Future studies are planned to further investigate the possible use of currently available FDA-approved HDAC inhibitors in the Pitt-Hopkins mouse model, Sweatt said.

The study was supported by the Defense Advanced Research Projects Agency (DARPA), the National Institutes of Health (grants MH57014 and MH104158), Civitan International, the Simons Foundation, McKnight Brain Research Foundation and the Pitt-Hopkins Research Foundation.

http://news.vanderbilt.edu/2016/08/study-suggests-new-way-to-treat-rare-autism-disorder/

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MDBR Request for Application (RFA)

UPenn’s 2016 Million Dollar Bike Ride Pilot Grant Program is now open!  The Pitt Hopkins Research Foundation has participated every year, since the start of this incredible program. The MDBR Pilot Grant Program provides a one-year grant to support research related to a rare disease represented in the 2016 Million Dollar Bike Ride. Number of awards and dollar amounts vary per disease based on fundraising totals by each disease team.

Eligibility: All individuals holding a faculty-level appointment at an academic institution or a senior scientific position at a non-profit institution or foundation are eligible to respond to this RFA.

Submit your Letter of Interest (LOI) via the link below no later than Friday, September 16, 2016 by 8pm EST.

Please visit UPenn’s Orphan Disease Center website to apply:  http://www.med.upenn.edu/orphandisease/rare-disease-overview.html

 

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MAHER LAB IDENTIFIES POTENTIAL DRUG TARGETS FOR PITT HOPKINS

Study Identifies Potential Treatment for Autism Spectrum Disorder

Lieber Institute investigators designed an innovative methodology that identifies the first potential treatment for Pitt-Hopkins syndrome, a type of autism.
10 March 2016

BALTIMORE—March 10, 2016—The Lieber Institute for Brain Development (LIBD) released today the results of an innovative study that may lead to a clinical trial within a relatively short time for the treatment of Pitt-Hopkins syndrome (PTHS), a type of autism spectrum disorder.

There are currently no medications available to treat the cognitive and behavioral deficits associated with PTHS, which is characterized by intellectual disability, developmental delays and communication deficits. The Lieber Institute’s study is the first to identify specific proteins that represent potential therapeutic targets for Pitt-Hopkins and possibly other neuropsychiatric disorders, including other forms of autism and schizophrenia. Lieber Institute scientists show that by modifying these proteins, abnormalities related to the Pitt-Hopkins gene are reversed.

The study, published today in the journal Neuron, is titled “Psychiatric Risk Gene Transcription 4 Regulates the Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1.” The paper can be found online here http://www.cell.com/neuron/fulltext/S0896-6273(16)00138-0.

In contrast to prior strategies for finding treatments for autism, which have mainly focused on trying to correct the genetic abnormality itself, Lieber Institute scientists took a novel approach to understand the mechanism responsible for the cognitive and behavioral deficits. In genetically modified rats, they identified abnormalities in brain cell function after birth that are potentially responsible for the cognitive and social abnormalities. Specifically, they found an ion channel protein not normally present in the brain to be overly active, disrupting nerve cell function. This particular ion channel is normally controlled by Transcription 4 (TCF4), the gene that is mutated in Pitt-Hopkins. When they administered drugs targeting this and another disrupted ion channel, or when they used genetic editing approaches to render the channels less active, the abnormal brain cells were restored to normal.

“These findings are a significant step toward developing effective treatments for Pitt-Hopkins and potentially other autism spectrum disorders,” said Brady J. Maher, Ph.D., the study’s lead investigator. “The results suggest that giving a drug that will block these ion channels in patients with Pitt-Hopkins could make their cells behave normally again.”

Pitt-Hopkins is caused by mutations of the gene TCF4. Because it is a monogenic disorder (caused by a single gene), scientists can effectively identify the underlying biology of the disorder in animal and cell models. Researchers at the Lieber Institute used CRISPR/Cas9 gene editing technology and short hairpin RNA to specifically target TCF4 function in an in vivo rodent model of Pitt-Hopkins. They also developed a novel technique called iTRAP to identify the culprit ion channels in the central nervous system, specifically SCN10a and KCNQ1, as candidate genes for targeted therapy.

“We are strongly encouraged by the results of this study and are moving forward with a series of experiments designed to further characterize the therapeutic target that we have identified at the cellular level,” said LIBD Director and CEO Daniel R. Weinberger, M.D. “We are exploring approaches for a therapeutic trial in individuals with this condition. Drugs that block these channels already exist, so this is a rare opportunity to go from the laboratory to the clinic in relatively short order.”

This work was supported by the Lieber Institute as well as NIH/NIMH grants (K01MH086050 and R56MH104593), a NARSAD Young Investigator Grant and a Pitt-Hopkins Research Foundation Grant awarded to Maher, the study’s lead investigator.

About the Lieber Institute for Brain Development

The mission of the Lieber Institute for Brain Development and the Maltz Research Laboratories is to translate the understanding of basic genetic and molecular mechanisms of schizophrenia and related developmental brain disorders into clinical advances that change the lives of affected individuals. LIBD is an independent, not-for-profit 501(c)(3) organization and a Maryland tax-exempt medical research institute affiliated with the Johns Hopkins University School of Medicine.

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Media Contacts

Amy Snow Landa or Aaron Blank, The Fearey Group for the Lieber Institute

http://www.libd.org/research-activities/our-news/2016/study-identifies-potential-treatment-for-autism-spectrum-disorder

Another article from the Baltimore Sun: http://www.baltimoresun.com/health/blog/bs-hs-autism-treatment-20160310-story.html

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2016 PHRF GRANT AWARDEES

The Pitt Hopkins Research Foundation is thrilled to announce our 2016 Grant Awardees.  Three grants were given at 75K each by the PHRF, and two grants were given through the University of Pennsylvania, Million Dollar Bike Ride, at 50K each.  A total of $325,000 was awarded for Pitt Hopkins research this year:  

Tilly Hadlow Young Investigator Award:

Joseph Alaimo, Ph.D., Principal Investigator; Sarah Elsea, Ph.D., Co-Investigator/Mentor, Baylor College of Medicine, Awarded $75,000, PHRF

Delineating Therapeutic Targets using Global Metabolic Profiling in Pitt Hopkins syndrome:  Defining the cellular defects due to alterations in TCF4 function is paramount in order to determine the proper molecular and biochemical targets for therapeutic intervention in Pitt-Hopkins syndrome. To identify and characterize the biochemical and molecular dysfunction due to altered TCF4 function, we plan to take a clinical and translational approach by recruiting a cohort of individuals with PTHS in collaboration with the Pitt-Hopkins Research Foundation and current PTHS clinics, phenotypically and molecularly characterizing the cohort, and employing state-of-the-art metabolomics screening to identify pharmacologically targetable molecular and biochemical pathways. Our unique approach will utilize a special type of biochemical genetic test called global metabolomics assisted pathway screening (Global MAPS). Global MAPS is currently the most comprehensive small molecule screen available in the clinical setting and is only available through Baylor College of Medicine’s Biochemical Genetics Diagnostic Laboratory. Global MAPS surveys greater than 1000 small molecules in human plasma, pinpointing defects in pathways unmeasurable by standard clinical testing methods, offering a comprehensive and in-depth analysis of patient samples and metabolic status. Our overall goal is to employ Global MAPS analysis in patients with PTHS to identify novel pathway alterations and to understand the basis of TCF4 function in cells. In addition, our proposal will serve as a functional confirmation of current molecular findings in PTHS research, including RNA-sequencing and gene expression profiling, thereby refining the molecular and biochemical targets that would benefit most from therapeutic intervention. Our novel but complementary approach will promote additional analysis to identify points of data convergence among other research groups thereby expediting the process toward targeted therapeutic intervention and clinical trials. Any Pitt-Hopkins families interested in participating in metabolomics profiling are highly encouraged to contact either Drs. Sarah Elsea or Joseph Alaimo at Baylor College of Medicine using the following information: email: Alaimo@bcm.edu   Phone: 832-824-8936

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, PHRF

Characterization and Generation of PTHS Model Mice for Rational Therapeutic Discovery:  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:

Andrew John Kennedy, Ph.D., Principal Investigator; J. David Sweatt, Ph.D., Co-Principal Investigator, Evelyn F. McKnight Brain Institute, The University of Alabama at Birmingham, Awarded $75,000, PHRF

Investigating Therapies for Pitt-Hopkins Syndrome:  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.

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

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

Tõnis Timmusk, Ph.D., Principal Investigator; Mari Sepp, Ph.D., Co-Investigator, Tallinn University of Technology, Estonia, Awarded $50,000, UPenn, MDBR

Regulation of TCF4 transcriptional activity in neurons:  Transcription factor TCF4 (alias ITF2, SEF2 or E2-2) is a broadly expressed protein involved in the development and functioning of many different cell types. Recent studies point to important roles for TCF4 in the nervous system. Specifically, human TCF4 gene is implicated in susceptibility to schizophrenia and mutations in TCF4 cause Pitt-Hopkins syndrome (PTHS), a rare developmental disorder characterized by severe motor and mental retardation, typical facial features and breathing anomalies. The mutation may be in different parts of the gene, but it appears in only one allele. Whereas in many other genes the other, unaffected allele would be able to compensate for the defect, this is not the case in TCF4. This indicates that the protein encoded by the TCF4 gene is essential for the development of the nervous system, and that human development depends significantly on the amount of this protein in the brain and body. Our previous data have suggested that synaptic activation of nerve cells, that is the basis of brain function, leads to activation and phosphorylation of TCF4 protein. Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation turns many proteins on and off, thereby altering their function and activity. The current project is aimed to find out how the activity and phosphorylation of TCF4 protein is regulated inside nerve cells of the brain, and to characterize the phosphorylation pattern of activated TCF4. Additionally, we want to determine which genes are targeted by TCF4 in nerve cells after synaptic activation. Since Pitt-Hopkins syndrome manifests itself at an early stage, there are better chances for its treatment due to the greater plasticity of children’s brains. Increasing the amount and/or activity of the functional TCF4 protein produced from the healthy allele is among possible approaches to develop drugs for Pitt-Hopkins syndrome treatment. We believe that our project could lead to the discovery of novel possibilities for increasing the activity of TCF4 in nerve cells that could be useful to develop treatments for therapeutic intervention of Pitt-Hopkins syndrome.

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Kindal Kivisto Award for Promising Young Researchers

 

This year, The PHRF is deeply moved to award the “Kindal Kivisto Award for Promising Young Researchers,” in honor of Kindal Kivisto a young woman who died far too soon, at the age of 29 this past October. Kindal did not have Pitt Hopkins, but was close friends with the Sandiford family whose daughter, Finley was diagnosed in 2014. In light of this, her family asked that all donations at the funeral be made to the Pitt Hopkins Research Foundation. The outpouring of love and support for this special young woman was overwhelming.  A total of $25,000 was donated to the Pitt Hopkins Research Foundation in memory of Kindal.  Her family wrote to us during this time, and we will never forget them saying that hoped some good could come of this tragedy.

So this year, in honor of Kindal and her family, we are awarding a grant to Dr. Andrew Kennedy of the The Sweatt Lab at The University of Alabama, Birmingham in her name, with the knowledge that the promise taken from her may in some small way be countered by the incredible hope and promise this young researcher creates for our families every day.

Kindal and Family… Thank you for making this possible for our children. You will not be forgotten.

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