Devastating genetic illnesses in kids may be treatable in maturity

A devastating genetic condition called CDKL5 Deficiency Disorder (CDD) that occurs in early childhood can be significantly treatable even in adulthood, a new study from the University of Pennsylvania’s Perelman School of Medicine suggests.

CDD is caused by a mutation of a gene called CDKL5 that is believed to play an important role in controlling proper brain development during childhood. In the study, published today in the Journal of Clinical Investigation, researchers found compelling evidence that the gene is important in the brain even after childhood. When they switched off the gene in healthy adult mice, the mice developed severe neurological problems as seen in mice that are initially lacking the gene. Scientists then attempted to restore CDKL5 gene activity in young adult mice that had been deprived of it during their early life and found that the animals became mostly normal.

One of the big questions in any genetic disease concerns the curability of the disease and the extent of the window in which a therapeutic approach, such as gene therapy, can help patients. Fortunately, we found evidence in these mouse experiments that CDD is likely to be treatable after childhood. “

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

CDD is found in about 1 in 40,000 babies born. The disorder usually manifests itself within weeks of birth and encompasses a variety of intellectual and neurological disabilities, including restricted mobility and epileptic seizures. Patients usually use wheelchairs and need assistance in all activities of daily living.

In 2012, Zhou and colleagues created “Cdkl5 knockout” mice in which Cdkl5 has a function-destroying mutation, as observed in a CDD patient. The researchers found that the knockout mice had many of the same problems seen with human CDDs. Given that CDD is characterized by early and pervasive neurological disability, the extent to which CDD would be treatable, and if so, the window of treatment for treatment, remains unknown.

In the new study, Barbara Terzic, a PhD student in neuroscience, and other members of the Zhou laboratory examined the role of CDKL5 in mice after brain development. They first discovered that the gene in the mouse brain is active not only at a young age, but throughout life. They then found that in normal, healthy, six-week-old mice – at the beginning of the young adulthood of the mouse – switching off the gene triggers essentially the same CDD-like disorder that occurs in ordinary CDKL5 knockout mice with corresponding brain changes .

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

In other words, people with CDD may not only suffer from developmental disorders due to their childhood CDKL5 deficit, but also from persistent adult CDKL5 deficit – a deficit that a therapeutic approach could address in adults. In fact, the researchers found that if they silenced the gene in mice from conception so that the animals developed the usual CDD-like impairments, and then turned the gene back on at six weeks of age, the CDD-like ones Impairments largely disappeared. Working with Marc Fuccillo, MD, PhD, an assistant professor of neuroscience at Penn, and his student Felicia Davatolhagh, they also discovered the physiological basis for phenotypic reversal in mice. These results suggest that CDD is not only treatable, but also amenable to treatment after childhood.

Researchers are at least years away from developing gene replacement or gene reactivation therapy for CDD, an endeavor that would pose many technical challenges, including the daunting hurdles of providing treatments for the central nervous system. But the experiments by Zhou and colleagues are promising “proof of the principle” that restoring normal levels of CDKL5 activity in adulthood can reduce symptoms.

Zhou and colleagues performed their experiments on male mice, which allowed for easier analysis, but are now pursuing similar experiments on female mice. Although nine out of 10 CDD cases occur in women, these female cases are complicated by the fact that one copy of the X chromosome in female cells happens to be inactivated – a “mosaicism” that is incomplete and inherently difficult to achieve analyze loss of CDKL5 activity.

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

Source:

University of Pennsylvania

Journal reference:

Terzic, B., et al. (2021) The temporal manipulation of Cdkl5 shows essential functions after development and reversible deficits in connection with CDKL5 deficiency disorders. Clinical Investigation Journal. doi.org/10.1172/JCI143655.

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