Twenty “must-read” publications from 2020

#1 to #3:  Gene therapy and X reactivation:

Gene replacement ameliorates deficits in mouse and human models of cyclin-dependent kinase-like 5 disorder.

Gao Y et al., Brain

Proof-of-concept for a gene replacement approach to CDKL5 deficiency disorder.

Benke TA and Kind PC, Brain

  • First published proof of concept for AAV-mediated gene therapy for the treatment of CDKL5 Deficiency Disorder.

Artificial escape from XCI by DNA methylation editing of the CDKL5 gene.

Halmai et al., Nucleic Acids Res

  • Impressively detailed and well-executed study providing strong proof of concept in a human cellular context for specific reactivation of the X-inactivated CDKL5 allele using genome-targeting strategies.

#4:  Molecular function in the nucleus:

Epilepsy kinase CDKL5 is a DNA damage sensor which controls transcriptional activity at DNA breaks.

Khanam et al., BioRxiv (pre-peer review manuscript)

  • Identification of novel CDKL5 kinase substrates in the nucleus of human cells highlights the role of CDKL5 in regulating transcription elongation/processivity, including in response to UV-induced DNA damage.  Important implications for the global role of CDKL5, and primate-specific functions which might not be detectable in other animal models.

#5 to #9:  Molecular function in the periphery:

Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models.

La Montanara P, et al., Sci Transl Med

  • Detailed analysis of deficiencies in pain signaling resulting from the loss of CDKL5, including the specific knockout of CDKL5 expression in DRG neurons.

A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury.

Kim JY, et al., Nat Commun

CDKL5 controls RTEC fate during AKI.

Carney EF, Nat Rev Nephrol

Involvement of the CDKL5-SOX9 signaling axis in rhabdomyolysis-associated acute kidney injury.

Kim et al., Am J Physiol Renal Physiol

CDKL5: a promising new therapeutic target for acute kidney injury?

de Caestecker MP, Am J Physiol Renal Physiol

  • In this series of two primary research reports from the Pabla lab, and two reviews by experts in the field, the role of CDKL5 in mediating a cell death response in acute kidney injury is nicely demonstrated, including implicating CDKL5-directed degradation of the SOX9 pro-survival factor as being a key step.

#10 to #13:  CNS Function and seizure-like activity in mouse models

Dopaminergic loss of cyclin-dependent kinase-like 5 recapitulates methylphenidate-remediable hyperlocomotion in mouse model of CDKL5 deficiency disorder.

Jhang et al., Hum Mol Genet

  • This is the first detailed demonstration of functional disruptions in dopaminergic signaling due to loss of CDKL5.  Implications for this disruption on striatal signal transduction and functional outputs are discussed.

X-linked cellular mosaicism underlies age-dependent occurrence of seizure-like events in mouse models of CDKL5 deficiency disorder.

Terzic B, et al., Neurobiol Dis

Aged heterozygous Cdkl5 mutant mice exhibit spontaneous epileptic spasms.

Mulcahey PJ, et al., Exp Neurol

  • These two papers, from a collaboration between the Zhou and Coulter labs, demonstrate the EEG and behavioral characteristics of epileptic spasms or “seizure-like” events in female heterozygous CDKL5 ko mice when aged out to several months.

Seizures in Mouse Models of Rare Neurodevelopmental Disorders.

Fallah MS and Eubanks JH, Neuroscience

  • Published early in 2020, this is a nice review from the Eubanks lab on spontaneous or induced seizure/seizure-like behavior in animal models of different neurodevelopmental disorders, including CDKL5 Deficiency Disorder, before the publication of the studies above.

#14 to #16:  QOL, genotype/phenotype, and seizure-free CDD patient:

Exploring quality of life in individuals with a severe developmental and epileptic encephalopathy, CDKL5 Deficiency Disorder.

Leonard H, et al., Epilepsy Res

Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory?

MacKay CI, et al., Am J Med Genet A

Exploring genotype-phenotype relationships in the CDKL5 deficiency disorder using an international dataset.

MacKay CI, et al., Clin Genet

  • A series of important papers from Helen Leonard and Jenny Downs on epidemiology and genotype-phenotype relationships in CDD, as well as a provocative finding of mutations in the CDKL5 gene of a patient who presents with many of the symptoms associated with CDD – but not seizures.

#17 to #18:  Clinical studies, including NIH natural history study on Rett and Rett-related disorders (including CDD)

Comparison of core features in four Developmental Encephalopathies in the Rett Natural History Study.

Cutri-French C, et al., Ann Neurol

  • First report on data from CDD patients within the NIH-funded Developmental Encephalopathy natural history study.

Evoked Potentials and EEG Analysis in Rett Syndrome and Related Developmental Encephalopathies: Towards a Biomarker for Translational Research.

Saby et al., Front Integr Neurosci

  • A nice review on the pre-clinical and clinical data around the use of evoked potentials and EEG in Developmental Encephalopathies, including CDD, as functional biomarkers to aid therapeutic development.

#19:  The Voice of the Patient Report

CDKL5 Deficiency Disorder:  Voice of the Patient Report

  • This report, prepared by the Loulou Foundation and the patient advocacy group IFCR following the externally-led Patient-Focused Drug Development (PFDD) meeting with the FDA on November 1, 2019, summarizes the patient and caregiver perspective of living with CDKL5 Deficiency Disorder, including the symptoms of CDD that matter most to patients and families in their daily life, current treatment/therapy options, and the impact that meaningful therapeutics would have on their quality of life. 

#20:  The videos of presentations from the CDKL5 Forum 2020

CDKL5 Forum 2020

  • Registration in the CDKL5 Forum portal is required to view the videos; if you are not already registered in the portal, you can apply for membership by clicking here.