Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.
If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.
This week’s study is…
Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder–related deficits
We previously published about this research in a story titled “CDKL5 Could Be Treatable into Adulthood, Study Shows” which can be found here. The study was originally published in the medical science journal The Journal of Clinical Investigation. You can view the full text of the study here.
This research team was affiliated with the Perelman School of Medicine at the University of Pennsylvania.
What Happened?
CDLK5 deficiency disorder is a rare genetic illness that strikes early in the patient’s life, inflicting seizures and a host of developmental problems. CDKL5 is the name of the gene that is mutated in the disease which codes for a protein of the same name that is known to play a critical role in the development of normal brain function. However, no research has been conducted to evaluate the role that CDKL5 might play later in life.
This study sought to determine the role of CDKL5 after the completion of development. The research team utilized mouse models of CDLK5 deficiency disorder (CDD) in order to conduct the study. In male mice, the scientists switched off the CDKL5 gene. They found that the mice developed major neurological issues that were comparable to the condition found in a mouse model of CDD, in which the mice have the gene switched off from birth. The researchers used male mice because the mutation is found on the X chromosome; therefore, the changes that the mutation causes are easier to analyze in male specimens.
In the next phase of the study, the scientists switched on CDLK5 in CDD mouse model mice and found that the animals regained most of their normal neurological function once CDKL5 was restored. They found that this restoration had to be done gradually; a sudden change in expression was fatal. These findings appear to demonstrate that CDKL5 continues to play a critical role in adulthood, and is likely critical for proper synaptic signaling, among other functions. In addition, the research demonstrated that the effects of CDKL5 could be nearly completely reversed and that treatment for the disorder could continue later in life.
About CDKL5 Deficiency Disorder
CDKL5 deficiency disorder is a genetic disorder which is characterized by intellectual disability, seizures, and developmental delays. As the name suggests, the disorder is linked to mutations of the CDKL5 gene which usually occurs spontaneously and is not inherited from a person’s parents. Symptoms become noticeable in the first few months of life. Females are affected more frequently than males, but males tend to have more severe symptoms. These symptoms can include seizures (1-5 per day), constipation, distinctive facial features, reflux, teeth grinding, and problems with feeding and sleeping. Treatment options for CDKL5 deficiency disorder are limited and are primarily focused on minimizing symptoms. Some patients may require a feeding tube. There is a serious need for new and more effective therapies to treat this disorder. In order to learn more about CDKL5 deficiency disorder, click here.
Why Does it Matter?
The results of this research can serve as a proof of concept for the development of future treatment, such as a gene therapy, that could potentially replace the mutated gene in patients and trigger a reversal of the disorder’s effects, as was demonstrated using the mouse model in this study. Before, it was not certain that the symptoms of CDD could ever be reversed. The findings also will allow physicians greater confidence in continuing treatment in adult patients. In addition, this gives some greater leeway in the timing of treatment overall.
One aspect of the research that is worth noting is the use of male mice. While this simplified the identification of signs and symptoms for the purposes of the study, around 90 percent of CDD cases actually occur in females. Since females with the disease will see one X chromosome inactivated at random in the cells, this makes for a much less defined loss of CDKL5 function. The scientists plan to conduct research next using female mice and also plan to study the impacts of CDKL5 reactivation later in adulthood.
While a gene therapy for this disorder is likely to still be several years out, the findings from this research provide a valuable building block.
“One of the big questions for any genetic disease concerns the curability 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 likely treatable, even after childhood.” – Zhaolan ‘Joe’ Zhou, PhD, senior author and Professor of Genetics
