CDKL5 Disorder: a Novel Therapeutic Strategy to Improve Brain Development in a Newly Generated CDKL5 ko Mouse Model

Doctoral thesis OPEN
De Franceschi, Marianna (2016)

The cyclin-dependent kinase like-5 (CDKL5) disorder is a rare neurodevelopmental disease caused by mutations in the CDKL5 gene, located on the X-chromosome. The consequent unsuccessful CDKL5 protein expression in the nervous system leads to a severe encephalopathy, characterized by mental retardation, reduced motor abilities and early-onset intractable epilepsy. CDKL5 is highly expressed in the brain during the early postnatal stages of development and a recently developed Cdkl5 KO mouse model showed that CDKL5 plays a fundamental role in postnatal neurogenesis by affecting neural precursor survival and maturation, with impairment of learning, memory and motor control. To date no therapies are available to treat CDKL5 patients, but an innovative therapeutic approach of protein replacement therapy has recently emerged, enabling the trans-vascular delivery of an exogenous protein to the brain following a simple systemic injection. It has been discovered that certain proteins and peptides can be efficiently translocated across cell membranes by virtue of the presence of a Protein Transduction Domain (PTD). Exploiting a safe and well characterized PTD domain, we created a CDKL5 recombinant protein in order to compensate for the lack of CDKL5 in knockout mice. In the present study we show the successful development of a protein replacement therapy for CDKL5 disorder, that in the future may be rapidly and efficiently transferred to patients.
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