Penn study suggests CDKL5 deficiency disorder could be treated after childhood

PHILADELPHIA CREAM- A devastating genetic condition called CDKL5 deficiency disorder (CDD), which strikes in infancy, can be meaningfully treated even in adulthood, suggests new study from the University of Pennsylvania’s Perelman School of Medicine .

CDD is caused by a mutation in a gene called CDKL5, which is thought to play an important role in the proper development of the brain during childhood. In the study published today in the Clinical investigation journal, researchers have 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 like those seen in mice lacking the gene early in life. Scientists then attempted to restore CDKL5 gene activity in young adult mice who had been deprived of them throughout their lives, and found that the animals had mostly become normal.

“One of the big questions for any genetic disease is the curability of the disease and the extent of the time window within which a therapeutic approach, such as gene therapy, can help patients. Encouragingly, we have found evidence from these experiments in mice that CDD is likely treatable even after childhood, ”said lead author. Zhaolan “Joe” Zhou, PhD, professor of genetics at Penn.

CDD is present in approximately 1 in 40,000 babies born. The disorder usually manifests itself within weeks of birth and includes a host of intellectual and neurological disabilities, including movement disorders and seizures. Patients generally use wheelchairs and need support with all activities of daily living.

Zhou and his colleagues in 2012 generated “Cdkl5 knockout mice “in which Cdkl5 has a function-destroying mutation like that seen in a CDD patient. The researchers found that the knockout mice exhibited many of the same problems seen in human CDDs. Since CDD is characterized by early and profound neurological disturbances, the extent to which CDD would be treatable and, if so, the time window for treatment remains unknown.

In the new study, Barbara Terzic, a graduate student in neuroscience, and other members of the Zhou lab investigated CDKL5in mice after brain development. They discovered, first of all, that the gene is active in the mouse brain not only early in life, but throughout life. They then found that in normal, healthy six-week-old mice – in the early adulthood of the mouse – deactivation of the gene triggers the emergence of essentially the same CDD-like disorder seen in ordinary mice. 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 deficit during childhood but also a CDKL5 deficit in adulthood – a deficiency that could be corrected in adults by a therapeutic approach. Indeed, the researchers found that when they silenced the gene in mice, from conception, so that the animals developed the usual CDD-like deficiencies, then reactivated the gene at the age of six weeks, CDD-type deficiencies have mostly disappeared. In collaboration with Marc Fuccillo, MD, Ph.D., assistant professor of neuroscience at Penn, and his student Felicia Davatolhagh, they also discovered the physiological basis of phenotypic inversion in mice. These results suggest that CDD is not only treatable but also lends itself to treatment even after childhood.

Researchers still have at least years to develop gene replacement or reactivation therapy for CDD, an endeavor that would pose many technical challenges, including the formidable hurdles involved in delivering treatments to the central nervous system. But the experiments of Zhou and his colleagues are a promising “proof of principle” that restores a normal level of. CDKL5 activity in adulthood can reduce the signs of the disease.

Zhou and his colleagues conducted their experiments on male mice, which allowed for simpler analysis, but are now continuing similar experiments on female mice. Although nine out of 10 CDD cases occur in women, these female cases are complicated by the fact that in female cells a copy of the X chromosome is randomly inactivated – a ‘mosaicism’ which leads to one being analyzed, the loss of CDKL5 activity.

“We also plan to examine the effects of CDKL5 further reactivation in adulthood in mice, ”Zhou said.

The research was supported by the Loulou Foundation, the International Research Foundation CDKL5, the Center for Research on Intellectual and Developmental Disabilities of CHOP / Penn and the National Institutes of Health (U54HD086984, R01NS102731).

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research and excellence in patient care. Penn Medicine consists of Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the country’s first medical school) and the University of Pennsylvania Health System, which together form an $ 8.9 billion company.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to the US News & World Report’s survey of research-driven medical schools. The school is consistently among the top recipients of funding from the National Institutes of Health, with $ 496 million awarded in fiscal year 2020.

The University of Pennsylvania Health System patient care facilities include: University of Pennsylvania Hospital and Penn Presbyterian Medical Center, which is recognized as one of the nation’s top hospitals by US News & World Report: Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the country’s first hospital, founded in 1751. Other facilities and businesses include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is fueled by a talented and dedicated workforce of over 44,000 people. The organization has also forged alliances with top community health systems in southeastern Pennsylvania and southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community programs and activities. In fiscal 2020, Penn Medicine provided over $ 563 million to benefit our community.

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