Mon. Nov 29th, 2021

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A devastating genetic disease called CDKL5 deficiency disorder (CDD), which strikes in early childhood, can be treated significantly even in adulthood, suggests a new study from the Perelman School of Medicine at the University of Pennsylvania.

CDD is caused by the mutation of a gene called CDKL5, which is thought to play an important role in controlling proper brain development in childhood. In the study published today in Journal of Clinical InvestigationResearchers found compelling evidence that the gene is important in the brain, even after childhood. When they turned off the gene in healthy adult mice, the mice developed serious neurological problems such as those seen in mice lacking the gene from the beginning of life. The researchers then tried to reintroduce CDKL5 gene activity in young adult mice that had been deprived of it during early life and found that the animals mostly returned to normal.

“One of the big questions for any genetic disease concerns the cure of the disorder and the extent of the time window in which a therapeutic approach, such as gene therapy, can help patients. “said senior author Zhaolan” Joe “Zhou, PhD, professor of genetics at Penn.

CDD is found in about 1 in every 40,000 babies born. The disorder usually manifests itself within weeks of birth and includes a wide range of intellectual and neurological disabilities, including movement disorders and epileptic seizures. Patients usually use wheelchairs and require support for all daily activities.

Zhou and colleagues in 2012 generated “Cdkl5 knockout” mice in which Cdkl5 has a function-destroying mutation similar to that observed in a CDD patient. The researchers found that knockout mice show many of the same problems seen in human CDD. Given that CDD is characterized by early and profound neurological impairments, the extent of CDD that can be treated and, if so, the time window for treatment are unknown.

In the new study, Barbara Terzic, a neuroscience graduate student and other members of the Zhou Laboratory, investigated the role of CDKL5 in mice following brain development. They first discovered that the gene is active in the mouse’s brain not only in early life, but throughout life. They then found that in normal, healthy, six-week-old mice — in the early stages of the mouse’s young adulthood — switching off the gene triggers the appearance of essentially the same CDD-like disorder seen in normal CDKL5 knockout mice. with corresponding brain changes.

“This suggests that CDKL5 has an indispensable role in the adult brain,” Zhou said.

In other words, people with CDD may not only suffer from developmental disabilities due to their CDKL5 deficiency in childhood, but also from a persistent CDKL5 deficiency in adulthood – a deficit that can be remedied in adults by a therapeutic approach. The researchers actually found that when they were silent about the gene in mice, from conception, so that the animals developed the usual CDD-like attenuations and then turned on the gene again at six weeks of age, the CDD-like attenuations mostly went away. In collaboration with Marc Fuccillo, MD, Ph.D., an assistant professor of neuroscience at Penn and his student Felicia Davatolhagh, they also uncovered the physiological basis for phenotypic reversal in mice. These findings suggest that CDD can not only be treated but can also be treated, even after childhood.

Researchers are still at least years away from developing a gene replacement or gene reactivation therapy for CDD, an experiment that would bring many technical challenges, including the formidable obstacles associated with delivering treatments to the central nervous system. However, the experiments of Zhou and colleagues are a promising “principled proof” that restoring a normal level of CDKL5 activity in adulthood can reduce disease signs.

Zhou and colleagues performed their experiments with male mice, which allowed a more straightforward analysis, but are now following up with similar experiments on female mice. Although nine out of 10 CDD cases occur in women, these female cases are complicated by the accidental inactivation of a copy of the X chromosome in female cells – a “mosaicism” that leads to a less than complete and inherently hard to analyze, loss of CDKL5 activity.

“We also plan to look at the effects of CDKL5 reactivation later in adulthood in mice,” Zhou said.


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More information:
Barbara Terzic et al., Temporal manipulation of Cdkl5 reveals significant post-development functions and reversible CDKL5 deficiency-related deficits, Journal of Clinical Investigation (2021). DOI: 10.1172 / JCI143655

Provided by the Perelman School of Medicine at the University of Pennsylvania

Citation: Study suggests that genetic disease CDKL5 deficiency disorder can be treated after childhood (2021, October 15) retrieved October 17, 2021 from https://medicalxpress.com/news/2021-10-genetic-disease-cdkl5-deficiency- disorder.html

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