Novel pre-clinical model for CDKL5 Deficiency Disorder

Abstract

Cyclin-dependent kinase-like-5 (CDKL5) Deficiency Disorder (CDD) is a severe X-linked neurodegenerative disease characterized by early-onset epileptic seizures, low muscle tone, progressive intellectual disability, severe motor function and visual impairment. CDD affects approximately 1 in 60,000 live births with many patients dying by early adulthood. For many patients, quality of life is significantly reduced due to the severity of their neurological symptoms and functional impairment. There are no effective therapies for CDD with current treatments focusing on improving symptoms rather than addressing the underlying causes of the disorder. Zebrafish offer a number of unique advantages for high-throughput pre-clinical evaluation of potential therapies for human neurological diseases including CDD. In particular, the large number of zebrafish that can be produced, together with the possibilities for in vivo imaging and genetic manipulation, allows for the detailed assessment of disease pathogenesis and therapeutic discovery. We have characterised a loss of function zebrafish model for CDD, containing a nonsense mutation in cdkl5. cdkl5 mutant zebrafish display defects in neuronal patterning, microcephaly, and reduced muscle function caused by impaired muscle innervation. This study provides a powerful vertebrate model to investigate CDD disease pathophysiology and allow high-throughput screening for effective therapies.