Daniel J. LaveryPhD
CDKL5 deficiency is characterized by epileptic seizures which begin within days or months of birth, and by severe developmental delay affecting neurological functions such as motor control, speech, and cognitive ability. This disorder is caused by mutations in the CDKL5 gene which reduce or eliminate expression or function of the CDKL5 protein, an enzyme that is important for normal brain function. The CDKL5 gene is present on the X chromosome; most described CDKL5 patients are females (>80%), whereas boys with CDKL5 deficiency tend to show more severe symptoms. The seizures associated with CDKL5 are largely resistant to control with current anti-epileptic drugs. Likewise, there is no current treatment for the severe developmental delay or associated symptoms such as motor dysfunction. While approximately 1,500 patients have been diagnosed with CDKL5 deficiency globally, the prevalence is likely higher due to mis- and un-diagnosed cases.
The identification of causative mutations within the CDKL5 gene on the X chromosome has led to the proposal of several therapeutic strategies to treat and eventually cure the disorder. First, therapies to replace the mutated gene or protein with a functional version are being developed. This is an approach which has proven successful for certain diseases associated with the mutation of a single gene. Second, targeted genome editing to correct the mutation in affected cells has also been proposed, based on transformational technologies such as CRISPR-mediated site-directed DNA modification. Third, strategies are being investigated to target, in girls, the reactivation of the unmutated CDKL5 gene on the silenced X chromosome in a process called X reactivation.. Finally, drug repurposing efforts are underway using bioinformatic and systems biology approaches to identify drugs developed for other diseases which might be effective against one or more of the symptoms of CDKL5 deficiency.
The ODC has partnered with the Loulou Foundation to create the CDKL5 Program of Excellence (PoE) within the ODC. The PoE is tasked with driving the development of effective therapeutic strategies for the treatment of CDKL5 deficiency. Together, the ODC and the Loulou Foundation have awarded and managed over 20 grants in the last two years totaling over $5 million, which have served to advance the understanding of CDKL5 under normal and pathological conditions, to generate the necessary tools for disease modeling and drug discovery, and to advance therapeutic development in the strategic domains described above.