New Research Finds Gene Therapy Could Treat Pitt-Hopkins Syndrome

DNA Gene Therapy Concept

A new study has shown that gene therapy may be able to prevent or reverse many of the harmful effects of Pitt-Hopkins syndrome.

New research from Ben Philpot’s UNC Neuroscience Center lab, Ph.D., finds restoring lost gene activity prevents many signs of disease in an animal model of Pitt-Hopkins syndrome, a rare, single-celled neurodevelopmental condition.

Pitt-Hopkins syndrome is a rare genetic condition caused by a mutation in the TCF4 gene on chromosome 18. Pitt-Hopkins syndrome is characterized by developmental delay, possible respiratory concerns such as episodic hyperventilation and / or shortness of breath, recurrent epileptic seizures / epilepsy. , gastrointestinal difficulties, lack of speech, and characteristic facial features. Children diagnosed with Pitt-Hopkins syndrome often have a happy and lively attitude with frequent smiles and laughter.

The prevalence of Pitt-Hopkins syndrome in the general population is unclear. However, some estimates place the incidence of Pitt-Hopkins syndrome between 1 in 34,000 and 1 in 41,000. The disease affects both men and women and is not limited to a single ethnic group.

Pitt Hopkins syndrome is classified as Autism Spectrum Disorder, and some people who have it have been diagnosed with Autism, “atypical” autism traits and / or Sensory Integral Failure. Many researchers believe that treatment of Pitt Hopkins syndrome will lead to treatments for similar disorders due to its genetic link to autism and other conditions.

For the first time, researchers at the University of North Carolina School of Medicine has shown that postpartum gene therapy may be able to prevent or reverse many of the negative effects of Pitt-Hopkins syndrome, a rare genetic disorder. Severe developmental delay, intellectual disability, respiratory and motor abnormalities, anxiety, epilepsy and moderate but characteristic facial abnormalities are all symptoms of this. autism spectrum disorder.

The scientists who published their results in the journal eLifecreated an experimental, genterapieca a technique to restore normal gene function in people with Pitt-Hopkins syndrome. The drug prevented the emergence of disease indicators such as anxiety-like behavior, memory impairment, and abnormal gene expression in affected brain cells in newborn mice that would otherwise model the syndrome.

“This first-of-its-kind evidence suggests that restoring normal levels of the Pitt-Hopkins syndrome gene is a viable therapy for Pitt-Hopkins syndrome that otherwise has no specific treatment,” said senior author Ben Philpot, Ph.D. .D. , Kenan Distinguished Professor of Cell Biology and Physiology at the UNC School of Medicine and Assistant Director of the UNC Neuroscience Center.

Cerba Protein Cre

Brain section image: Cre protein (green) delivered to cells as gene therapy by AAV. Credit: Philpot Lab (UNC School of Medicine)

Most genes are inherited in pairs, one copy from the mother and one from the father. Pitt-Hopkins syndrome arises in a child when one copy of the TCF4 gene is missing or mutated, resulting in an insufficient level of TCF4 protein. Typically, this removal or mutation occurs spontaneously in the parent egg or sperm cell before conception, or in the earliest stages of embryonic life after conception.

Only about 500 cases of the syndrome have been reported worldwide since it was first described by Australian researchers in 1978. But no one knows the true prevalence of the syndrome; some estimates suggest there could be more than 10,000 cases in the United States alone.

Because TCF4 is a “transcription factor” gene, a master switch that monitors the activities of at least hundreds of other genes, its disruption from the onset of development leads to many developmental abnormalities. In principle, preventing these abnormalities by restoring normal TCF4 expression as soon as possible is the best treatment strategy – but it has not been tested yet.

Philpot’s team, led by first author Hyojin (Sally) Kim, Ph.D., a graduate student in the Philpot lab during the study, developed a mouse model of Pitt-Hopkins syndrome in which the level of the mouse version of TCF4 could be . reliably halved. This mouse pattern showed many typical signs of the disorder. Restoring the full activity of the gene from the beginning of embryonic life completely prevented these signs. The researchers also found evidence in these initial experiments that gene activity had to be restored in essentially all kinds of neurons to prevent the appearance of Pitt-Hopkins signs.

Subsequently, the researchers set up a proof-of-concept experiment modeling a real-world gene therapy strategy. In engineered mice in which approximately half of the expression of the mouse version of Tcf4 was turned off, the researchers used a virus-delivered enzyme to re-enable the missing expression in neurons immediately after the mice were born. Analyzes of the brain showed this restoration of activity over the next few weeks.

Even though the treated mice had moderately smaller brains and bodies compared to normal mice, they did not develop many of the abnormal behaviors seen in untreated Pitt-Hopkins model mice. The exception was congenital nest-building behavior, in which the treated mice appeared abnormal at first, although their abilities were normalized within a few weeks.

The treatment at least partially reversed two other abnormalities seen in untreated mice: altered levels of the genes regulated by TCF4 and altered patterns of neuronal activity as measured in electroencephalographic (EEG) recordings.

“These findings give hope that future gene therapy will provide significant benefits to individuals with Pitt-Hopkins syndrome even when delivered postpartum; it will not require diagnosis and treatment in the womb,” Kim said.

Philpot and his lab now plan to investigate the effectiveness of their strategy when applied to Pitt-Hopkins mice in later stages of life. They also plan to develop experimental gene therapy in which the human TCF4 gene itself will be delivered by a virus into a Pitt-Hopkins mouse model – a therapy that could ultimately be tested in children with Pitt-Hopkins syndrome.

“We will be working on gene therapy, but our findings here suggest that there are other TCF4 restorative approaches that could work, including treatments that enhance the performance of the remaining good copy of TCF4,” Philpot said.

The research was supported by the Ann D. Bornstein Grant of the Pitt-Hopkins Research Foundation, the National Institute of Neurological Disorders and Stroke (R01NS114086), the Estonian Research Council and the Orphan Disease Center at the Perelman School of Medicine at the University. of Pennsylvania (MDBR-21-105-Pitt Hopkins).

Reference: “Rescue behavioral and electrophysiological phenotypes in Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression” by Hyojin Kim, Eric B Gao, Adam Draper, Noah C Berens, Hanna Vihma, Xinyuan Zhang, Alexandra Higashi-Howard, Kimberly D Ritola, Jeremy M Simon, Andrew J Kennedy and Benjamin D Philpot, May 10, 2022, eLife.
DOI: 10.7554 / eLife.72290

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