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 and report here.

Study suggests new way to treat rare autism disorder

by Bill Synder 

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.

Read more here.

Originally published on the Pitt Hopkins Research Foundation website.

Study Identifies Potential Treatment for Autism Spectrum Disorder

LieberInstitutelogoBALTIMORE—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.


Media Contacts

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