DNA Gene Therapy Concept

Possible treatment for autism: New research finds gene therapy can treat Pitts Hopkins syndrome

A new study shows that gene therapy may be able to prevent or reverse many of the harmful effects of Pitts Hopkins syndrome

New research from the UNU Center for Neurosciences Laboratory in Ben Philpott, PhD, finds that restoring lost gene activity prevents many markers of disease in an animal model of Pitt Hopkins syndrome, a rare, single-gene 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 delays, possible respiratory concerns such as occasional hyperventilation and/or waking breath, frequent seizures/epilepsy, gastrointestinal difficulties, lack of speech Distinctive facial features. Children with Pitts 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 have been diagnosed with autism, “atypical” features of autism, and/or impaired sensory integration. Many researchers believe that treating 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 have 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 movement disturbance, anxiety, epilepsy, and mild and characteristic facial abnormalities are all symptoms of this autism spectrum disorder.

Scientists who published their findings in the journal eLifeHe devised an experimental gene therapy-like technique to restore the normal function of the genetic deficiency 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 model the syndrome.

“This first proof-of-principle demonstration suggests that restoring normal levels of the Pitt Hopkins syndrome gene is a viable treatment for Pitt Hopkins syndrome, which otherwise has no specific treatment,” said senior author Ben Philpott, Ph. Kinan Distinguished Professor of Cell Biology and Physiology at the University of North Carolina School of Medicine and associate director of the University of North Carolina Center for Neuroscience.


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

Most genes are inherited in pairs, one copy from the mother and one from the father. Pitt Hopkins syndrome appears in a child when one copy of the TCF4 gene is missing or mutated, resulting in an insufficient level of the TCF4 protein. This deletion or mutation usually occurs spontaneously in the parental egg or 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 there may be more than 10,000 cases in the United States alone.

Since TCF4 is a ‘transcription factor’ gene, a master switch that controls 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 expression of TCF4 as soon as possible is the best treatment strategy—but it has not yet been tested.

The Philpot team, led by first author Hyojin (Sally) Kim, Ph.D., and a graduate student in Philpot’s lab during the study, developed a mouse model of Pitt-Hopkins syndrome in which the murine transcript level of TCF4 could be reliably halved. This mouse model showed several typical signs of the disorder. Restoring the full activity of the gene from the beginning of fetal life prevented these signs from occurring completely. The researchers also found evidence in these initial experiments that restoring gene activity in essentially all types of neurons is necessary to prevent the Pitts Hopkins signs from appearing.

Next, the researchers set up a validation experiment to model a real-world gene therapy strategy. In engineered mice in which nearly half of the murine transcript expression of Tcf4 was turned off, the researchers used a virus-transmitted enzyme to bring the lost expression back into neurons, soon after the mice were born. Brain analyzes showed recovery of activity over the next several weeks.

Although the treated mice had relatively 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 the innate nest-building behaviour, in which the treated mice appeared abnormal initially, although their abilities were restored to normal within a few weeks.

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

These findings offer hope that future gene therapy will provide significant benefits to individuals with Pitts Hopkins syndrome even when performed after birth; “It wouldn’t require in-utero diagnosis and treatment,” Kim said.

Philpot and his lab now plan to explore the effectiveness of their strategy when applied to Pitt-Hopkins mice in later life. They also plan to develop an experimental gene therapy in which the human TCF4 gene itself is transferred via a virus into a Pitt-Hopkins mouse model — a treatment that could eventually be tested in children with Pitt-Hopkins syndrome.

“We’ll be working on a gene therapy, but our results here suggest that there are other ways to restore TCF4 that could work, including treatments that boost the activity of the remaining good TCF4 transcript,” Philpott 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 the university’s Perelman School of Medicine. Pennsylvania (MDBR-21-105-Pitt Hopkins).

Reference: “Rescuing behavioral and electrophysiological phenotypes in a mouse model of Pitts Hopkins syndrome 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 de Philpott, 10 May 2022, Available here. eLife.
DOI: 10.7554 / eLife.72290

2022-06-05 04:24:47

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