Study seeks to identify gene therapy for Pitt-Hopke syndrome

A group of researchers from Campinas State University (Unicamp) and University of California San Diego in the United States is currently studying a mutation in the TCF4 gene, which causes Pitt Hopkins syndrome.

Pitt Hopkins syndrome is a neurodevelopmental disorder with features of autism spectrum disorder (ASD). It has a rare genetic cause, causing cognitive impairment, neuropsychiatric delay, speech deficiency, convulsive seizures, and respiratory disorders in the patient. It is estimated that the syndrome affects 1 in 30,000 people.

“All patients with this syndrome have a mutation in this gene. This gene is also associated with other diseases such as bipolar disorder and schizophrenia. It is important to remember that a hereditary disease is different from saying that the disease is hereditary. It is hereditary. It is when it is inherited from the father and the mother.” In this case, it is not. The parents do not have the genetic mutation, and they do not carry this genetic problem,” explained Fabio Papis, a professor at the Unicamp Biology Institute and one of the study coordinators.

With the knowledge of the mechanism that causes this condition, the researchers began studying this TCF4 gene in the laboratory. In this study they used not animals, but human cells. “The brain of a laboratory animal does not develop in the same way as the brain of a child with this syndrome. This then led us to study the patients’ cells. These cells were collected and grown in the laboratory and transformed into stem cells so that we could have the so-called brain organelles. He explained that the organelles It is a miniature version of the brain, but in a test tube, inside a lab.

Study seeks to identify gene therapy for Pitt Hopkins syndrome

Fabio Papis, Professor at the Unicamp Institute of Biology – Fulvia DIPillo / rights reserved

During this phase of the study, Babis and other researchers sought to devise and test a gene therapy that could reverse the effects caused by the mutation in the TCF4 gene. And in the lab, the tests were promising.

“Gene therapy can be done in many ways. You can simply replace the problematic gene by taking out that gene with another that is working properly. In the case of this disease, this is not possible because the gene is too large. In our work, we treat gene therapy in two other ways. In one of them, we insert A third gene in the cells of a sick individual. All of our cells contain two copies of each gene, including the TF4 gene: one we inherit from the father and one we inherit from the mother. In patients with this syndrome, one of the copies does not function properly. To compensate for this For the version that doesn’t work well, we researchers introduce a third, normal, functional version in cells, to compensate for a gene that doesn’t work well inside cells.”

The scientists also tested another strategy in the lab to try to reverse the effects of the mutation: They used a technology called CRISPR-Cas9, whose creators won the 2020 Nobel Prize in Chemistry, Babis said. .

To explain what happened in this strategy, compare the two genes with two candles. “It is as if a person, in any cell, had two lit candles inside. In a patient with the syndrome, there is only one lit candle. What we did was make this candle, which was lit, burn twice as fast. The gene activity happens to be higher than the normal gene .then it compensates for the lack of activity of the defective gene inside the patient’s cell,” he said.

At the end of the experiments, the two methods used by the scientists (the introduction of a third gene and CRISPR) gave similar results. “All the same, with the same kind of results. Now clinical trials will determine which of the two methods will be effective for people to use.”

Clinical trials

Despite the promising in vitro results, the research still needs to undergo new tests, called clinical trials, when they are applied to human volunteers. This stage, according to Babes, can take between five or ten years to start showing results. A company from the United States, Ultragenics, has already licensed the project and will be responsible for this phase of studies, which have not yet begun as scheduled. The clinical phase is expected to be implemented in several countries, including Brazil.

In an interview with Brazil Agency and the National RadioThe researcher said the findings should also help treat other disorders such as schizophrenia, post-traumatic stress and bipolar disorder. “Patients with these other diseases have mutations in the same gene, and eventually may benefit from the same treatment,” he said.

Gene therapy in Brazil

The gene therapy began to be applied in Brazil in February of this year, against leukemia, when it was approved by the National Health Surveillance Agency (Anvisa). This treatment can cost up to $475,000. At the current exchange rate, this equates to more than 2 million Brazilian reals. But, according to Babes, until the study is complete, the price of gene therapies should be much lower. He also hopes that this type of treatment can be used in the Unified Health System (SUS).

The study was published in the journal Nature Communications It is supported by the São Paulo Research Foundation (Fapesp) and the National Council for Scientific and Technological Development (CNPq).

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