Saturday , June 25 2022

Disruptive genetic disease in children can be cured in adulthood


A devastating genetic disease called CDKL5 deficiency disorder (CDD), which occurs in early childhood, is significantly treatable even in adulthood, according to new research from the Perelman School of Medicine at the University of Pennsylvania.

It is caused by a mutation of a gene called CDD. CDKL5It is thought to play an important role in guiding appropriate brain development during childhood. In the study published today, Journal of Clinical ResearchResearchers have found convincing evidence that the gene is important in the brain even after childhood. When they turned the gene off in healthy adult mice, the mice developed serious neurological problems similar to those seen in mice missing the gene from the start of life. Scientists then tried to restore CDKL5 Gene activity in young adult mice deprived of it during their early life and animals were found to mostly become normal.

One of the big questions for any genetic disease concerns the treatability of the disorder and the extent of the time window in which a therapeutic approach such as gene therapy can help patients. Encouragingly, we found evidence from these mouse experiments that CDD is treatable even after childhood.”

Zhaolan “Joe” Zhou, PhD, Senior Author, Professor of Genetics at Penn

CDD is found in about 1 in every 40,000 babies born. The disorder usually appears in the weeks after birth and includes a range of mental and neurological disabilities, including movement disorders and epileptic seizures. Patients often use wheelchairs and need support in all activities of daily living.

In 2012, Zhou et al.cdkl5 knockout mice cdkl5 He has a disabling mutation similar to that observed in the CDD patient. The researchers found that the knockout mice showed many of the problems seen in human CDD. Given that CDD is characterized by early and profound neurological disabilities, the extent to which CDD is curable and, if so, the time window of treatment is unknown.

In the new study, Barbara Terzic, a neuroscience graduate student, and other members of the Zhou lab investigated CDKL5Role in mice after brain development. First, they discovered that the gene is active in the mouse brain throughout life, not just early life. They then found that turning off the gene in normal, healthy, six-week-old mice — at the onset of mouse young adulthood — triggered the onset of the CDD-like disorder seen mainly in ordinary humans. CDKL5 knockout mice with corresponding brain changes.

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

In other words, people with CDD may not only suffer from developmental disorders. CDKL5 childhood, but also an ongoing CDKL5 deficiency in adulthood-; a deficiency in adults that can be remedied with a therapeutic approach. Indeed, when the researchers silenced the gene in mice before conception, so that the animals developed the usual CDD-like disorders, then turned the gene back on at six weeks of age, they found that the CDD-like disorders mostly disappeared. In collaboration with Marc Fuccillo, MD, PhD, assistant professor of Neuroscience at Penn, and his student Felicia Davatolhagh, they also uncovered the physiological basis of phenotypic reversal in mice. These findings suggest that CDD is not only treatable, but also amenable to treatment even after childhood.

At least years after researchers developed a gene-switching or gene-reactivation therapy for CDD, an effort that will present many technical challenges, including the formidable hurdles of delivering a cure to the central nervous system. But experiments by Zhou and colleagues are a promising “proof of principle” that restores a normal level. CDKL5 activity in adulthood can reduce disease symptoms.

Zhou and colleagues conducted their experiments in male mice, which allowed for a simpler analysis, but are now following similar experiments in female mice. Although nine out of 10 cases of CDD occur in females, these female cases are complicated by the fact that one copy of the X chromosome is randomly inactivated in female cells -; a ‘mosaism’ that leads to less than completeness and naturally a ‘mosaism’. difficult to analyze, lost CDKL5 activity.

“We plan to look at the effects as well” CDKL5 further reactivation to adulthood in mice,” Zhou said.


University of Pennsylvania

Journal reference:

Terzic, B., et al. (2021) Temporal manipulation of Cdkl5 reveals key post-developmental functions and deficits associated with reversible CDKL5 deficiency disorder. Journal of Clinical Research.

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