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New research shows that gene therapy could treat Pitt-Hopkins syndrome

The concept of DNA gene therapy

New study shows gene therapy can prevent or reverse many of the harmful effects of Pitt-Hopkins syndrome

New research from the UNC Neuroscience Center in Ben Philpot, Ph.D., finds that restoring lost gene activity prevents many signs of disease in an animal model of Pitt-Hopkins syndrome, a rare condition of single-gene neurological development .

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, potential respiratory problems, such as episodic hyperventilation and / or shortness of breath. recurrent seizures / epilepsy, gastrointestinal difficulties, speech loss and distinctive facial features. Children diagnosed with Pitt-Hopkins syndrome often have a happy, lively attitude, smiling and laughing frequently.

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

Pitt Hopkins Syndrome is classified as an autism spectrum disorder, and some people with it have been diagnosed with autism, “atypical” autistic traits, and / or sensory integration dysfunction. Many researchers believe that treating Pitt Hopkins syndrome will lead to treatments for similar disorders because of its genetic link to autism and other conditions.

For the first time, researchers at the University of North Carolina Medical School have shown that postnatal gene therapy can prevent or reverse many of the negative effects of Pitt-Hopkins syndrome, a rare genetic disorder. Severe developmental delay, intellectual disabilities, respiratory and movement abnormalities, anxiety, epilepsy and moderate but distinctive facial abnormalities are all symptoms of this autism spectrum disorder.

Scientists, who published their findings in the journal Elif, created an experimental technique, similar to gene therapy, to restore the normal function of the deficient gene in people with Pitt-Hopkins syndrome. The drug prevented indicators of disease, such as anxiety-like behavior, memory impairment, and abnormal gene expression patterns in affected brain cells in newborn mice that would otherwise shape the syndrome.

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

Brain Protein Cre

Brain section image: Cre (green) protein 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 occurs in a child when a copy of the TCF4 gene is missing or mutated, resulting in an insufficient level of TCF4 protein. Usually, this deletion or mutation occurs spontaneously in the parental egg or in the sperm cell before conception or in the early 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 that there may be more than 10,000 cases in the United States alone.

Because TCF4 is a “transcription factor” gene, a major switch that controls the activities of at least hundreds of other genes, its early discontinuation leads to many developmental abnormalities. In principle, preventing those abnormalities by restoring normal TCF4 expression as early as possible is the best treatment strategy - but it has not yet been tested.

Philpot’s team, led by first author Hyojin (Sally) Kim, Ph.D., a graduate student at 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 definitely halved. This mouse model showed many typical signs of the disorder. Restoring the entire activity of the gene from the beginning of embryonic life completely prevented these signs. The researchers also found evidence in these early experiments that gene activity must be restored in essence in all types of neurons to prevent the appearance of Pitt-Hopkins signs.

The researchers then set up a proof-of-concept experiment modeling a real-world gene therapy strategy. In the modified mice, in which about half of the expression of the mouse version of Tcf4 was stopped, the researchers used a virus-released enzyme to reactivate the missing expression in the neurons immediately after the mice were born. Brain tests showed this recovery in the next few weeks.

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

Treatment reversed at least two other abnormalities seen in untreated mice: altered levels of TCF4-regulated genes and altered patterns of neural activity, as measured by electroencephalograph (EEG) recordings.

“These findings provide hope that future gene therapy will provide significant benefits to people with Pitt-Hopkins syndrome, even when delivered postnatal; will not require diagnosis and treatment in utero, “said Kim.

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

“We are working on gene therapy, but our results suggest that there are other approaches to restoring TCF4 that might work, including treatments that stimulate the activity of the remaining TCF4 copy,” Philpot said.

The research was supported by 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 Center for Orphan Diseases at Perelman University School of Medicine. of Pennsylvania (MDBR-21-105-Pitt Hopkins).

Reference: “Saving Behavioral and Electrophysiological Phenotypes in a Pitt-Hopkins Syndrome Mouse Model by Genetically Restoring 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, Elif.
DOI: 10.7554 / eLife.72290

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