New research shows gene therapy may 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 the UNC Neuroscience Center lab of Ben Philpott, PhD, has found that restoring lost gene activity prevents multiple disease signals in an animal model of Pitt-Hopkins syndrome, a rare, single-gene neurodevelopmental condition.

Pitt-Hopkins syndrome is a rare genetic condition caused by mutations in the TCF4 gene on chromosome 18. Pitt-Hopkins syndrome is characterized by developmental delay, possible respiratory concerns such as episodic hyperventilation and/or breathing difficulties while awake, recurrent seizures/epilepsy, gastrointestinal difficulties, speech deficits and distinctive facial features. Children with Pitt-Hopkins syndrome often have a happy and lively attitude with smiles and laughs.

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 who have it have been diagnosed with autism, ‘atypical’ autistic features, and/or sensory integration dysfunction. Many researchers believe that treating Pitt Hopkins syndrome will lead to treatments for similar disorders because of the genetic link to autism and other conditions.

For the first time, researchers University of North Carolina School of Medicine have shown that postnatal 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 locomotor abnormalities, anxiety, epilepsy, and moderate but distinct facial abnormalities are all symptoms. autism spectrum disorder,

Scientists publishing their findings in the Journal eLifemade an experimental, gene-therapy-like Techniques to restore normal function of the gene deficiency in people with Pitt-Hopkins syndrome. The drug prevented the onset of disease indicators such as anxiety-like behavior, memory loss, and abnormal gene expression patterns in afflicted brain cells in newborn mice that would otherwise model the syndrome.

“This first, proof-of-principle demonstration 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 senior author Ben Philpott, Ph. .D. , Kenan Distinguished Professor of Cell Biology and Physiology at the UNC School of Medicine and associate director of the UNC Neuroscience Center.

brain protein cray

Brain section image: The protein Cre (green) delivered to cells as a form of gene therapy via AAV. credit: Philpott 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 insufficient levels of the TCF4 protein. Usually, this deletion or mutation occurs spontaneously in a parent’s 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 recorded worldwide since it was first described by Australian researchers in 1978. But no one knows the actual prevalence of the syndrome; Some estimates suggest that there may be as many as 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 beginning of development leads to many developmental abnormalities. In theory, preventing those abnormalities by restoring normal TCF4 expression as soon as possible is the best treatment strategy – but this has not yet been tested.

A graduate student in the Philpott laboratory during the study, first author Hyojin (Sally) Kim, Ph.D. Philpott’s team developed a mouse model of Pitt-Hopkins syndrome in which levels of the mouse version of TCF4 can be reliably halved. This mouse model showed many of the typical symptoms of the disorder. These signals can be completely stopped by restoring the full activity of the gene from the beginning of embryonic life. The researchers also found evidence in these preliminary experiments that preventing the emergence of Pitt-Hopkins signals required restoring gene activity in essentially all types of neurons.

Next, the researchers set up a proof-of-concept experiment modeling a real-world gene therapy strategy. In engineered mice, in which about half of the expression of the mouse version of Tcf4 was turned off, the researchers used a virus-delivered enzyme to switch the missing expression back into neurons again, just after the mice were born. Brain analysis showed this resumption of activity over the next several weeks.

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

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

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

Philpott and his lab now plan to explore the effectiveness of their strategy when applied to Pitt-Hopkins rats in later stages of life. They also plan to develop an experimental gene therapy in which the human TCF4 gene will be delivered by a virus into a Pitt-Hopkins mouse model — a therapy that could eventually be tested in children with Pitt-Hopkins syndrome.

“We will be working on a gene therapy, but our results here suggest that there are other TCF4-restoring approaches that may work, including treatments that promote the activity of the remaining, good TCF4 transcript,” Philpott said.

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

Reference: “Rescue of Behavioral and Electrophysiological Phenotypes in a Pitt-Hopkins Syndrome Mouse Model by Genetic Restoration of TCF4 Expression” by Hyujin Kim, Eric B. Gao, Adam Draper, Noah C. Berens, Hannah Vihma, Xinyuan Zhang, Alexandra Higashi-Howard. Kimberly D’Ritola, Jeremy M. Simon, Andrew J. Kennedy and Benjamin D. Philpott, May 10, 2022, eLife,
DOI: 10.7554/elife.72290

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