New research has shown that gene therapy can cure Pitt-Hopkins syndrome

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

A new study by Ben Philpott’s laboratory at the UNC Center for Neurology found that restoring lost gene activity prevents symptoms of many diseases in the animal model of Pitt-Hopkins syndrome, a rare, single-gene neurotransmitter condition.

Pitt-Hopkins syndrome is a rare genetic disease caused by a mutation in the TCF4 gene on chromosome 18. Pitt-Hopkins syndrome is characterized by developmental delays, potential respiratory problems such as episodic hyperventilation and / or respiratory arrest on awakening, recurrent seizures / epilepsy, gastrointestinal disorders, speech insufficiency, and distinctive facial features. Children with Pitt-Hopkins syndrome often smile, laugh, and be happy and lively.

The prevalence of Pitt-Hopkins syndrome in the general population is unclear. However, some estimates put the frequency 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 one ethnic group.

Pitt Hopkins syndrome is classified as a disorder of the autism spectrum, and some people with it have been diagnosed with autism, “atypical” autistic characteristics, and / or sensory integration dysfunction. Many researchers believe that the treatment of Pitt Hopkins syndrome leads to the treatment of similar diseases because it is genetically linked to autism and other conditions.

Researchers at the University of North Carolina School of Medicine have shown for the first time that postpartum gene therapy can prevent or reverse many of the side effects of Pitt-Hopkins syndrome, a rare genetic disorder. Severe developmental delays, mental disorders, respiratory and motor disorders, anxiety, epilepsy, and moderate but distinct facial disorders are all signs of this autism spectrum disorder.

The scientists published their findings in a journal eLife, Created an experimental, gene-therapy-like technique to restore the normal functioning of the gene deficiency in people with Pitt-Hopkins syndrome. The drug prevents the development of disease indicators in the brain cells of newborn mice, such as anxiety, memory impairment and abnormal gene expression, which models the syndrome in other ways.

“This first, evidence-based demonstration shows that restoring normal levels of the Pitt-Hopkins syndrome gene is the appropriate therapy for Pitt-Hopkins syndrome, meaning there is no specific treatment,” said senior author Ben Philpott, Ph.D. , Kenan is an Honorary Professor of Cell Biology and Physiology at the UNC School of Medicine and Deputy Director of the UNC Neurology Center.

Brain Protein Cre

Brain Division Image: The protein Cre (green) is delivered to cells as gene therapy through AAV. Credit: Philpot Lab (UNC Medicine School)

Most genes are inherited in pairs, one copy from the mother and one from the father. Pitt-Hopkins syndrome occurs when a child does not have a copy of the TCF4 gene or is mutated, resulting in insufficient levels of the TCF4 protein. Typically, this destruction or mutation occurs spontaneously in the ovum or sperm cell before the embryo, or in the very early stages of embryonic life after the embryo.

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

Since the TCF4 “transcription factor” gene is the main transmitter that controls the activity of at least hundreds of other genes, its disruption from the beginning of development leads to many developmental anomalies. In fact, restoring normal expression of TCF4 as early as possible is the best treatment strategy to prevent these anomalies, but it has not yet been tested.

Philpot’s team, led by the first author, Hojin (Sally) Kim, a graduate student at Philpot Laboratory during the study, developed a mouse model of Pitt-Hopkins syndrome, which may be the level of the TCF4 mouse version. reliably halved. This mouse model showed many typical signs of confusion. Restoration of full gene activity from the beginning of embryonic life completely prevented these symptoms. The researchers also found that in these early experiments, genetic activity had to be restored in all types of neurons to prevent the development of Pitt-Hopkins symptoms.

Then, the researchers created a conceptual evidence experiment to model real-world gene therapy strategies. In engineering mice, where about half of the Tcf4 version of the mouse was turned off, the researchers used a virus-delivered enzyme to process expression that was not present in neurons after the mice were born. Brain tests showed that activity was restored within the next few weeks.

Although the brains and bodies of the treated mice were slightly smaller than those of normal mice, they did not develop much of the abnormal behavior observed in untreated Pitt-Hopkins mice. Congenital nesting was unusual in that the treated mice initially seemed abnormal, but their abilities were restored within a few weeks.

Treatment eliminated at least two other abnormalities observed in partially untreated mice: the level of genes regulated by TCF4 and altered patterns of neuronal activity measured on electroencephalographic (EEG) records.

“These findings hope that future gene therapy will be of significant benefit to people with Pitt-Hopkins syndrome even after childbirth; It does not require diagnosis or treatment in the womb, ”Kim said.

Philpott and his lab now plan to study the effectiveness of the strategy used on Pitt-Hopkins mice in later life. They also plan to develop experimental gene therapy, in which the human TCF4 gene is transmitted through a virus to a Pitt-Hopkins mouse model – a therapy that could eventually be tested in children with Pitt-Hopkins syndrome.

“We’re working on gene therapy, but our results here show that there are treatments that increase the activity of the rest, including good TCF4 replication, other methods of TCF4-recovery,” Philpott said.

The study was conducted by Anne D. from the Pitt-Hopkins Research Foundation. Supported by Bornstein Grant, National Institute of Neurological Disorders and Stroke (R01NS114086), the Estonian Research Council and the Center for Orphans at the Perelman School of Medicine. Pennsylvania (MDBR-21-105-Pitt Hopkins).

Reference: Hojin Kim, Eric B. Gao, Adam Draper, Noah Si Berens, Hannah Wihma, Xinyuan Zhang, Alexandra Higashi-Howard Ritola, Jeremy M. Simon, Andrew Kennedy and Benjamin D Philpott, May 10, 2022, eLife.
DOI: 10.7554 / eLife.72290

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