Imperial College London
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ProfessorNicholasMazarakis

Faculty of Medicine, Department of Brain Sciences

Chair MolBioMedicine and Head of Gene Therapy
 
 
 
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Contact

 

+44 (0)20 7594 7024n.mazarakis Website

 
 
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Assistant

 

Mrs Hadeel Abdeen +44 (0)20 7594 7014

 
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Location

 

E402Burlington DanesHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Yunan:2020:brain/awaa028,
author = {Yunan, Gao Y and Irvine, E and Eleftheriadou, I and Naranjo, CJ and Hearn-Yeats, F and Bosch, L and Glegola, J and Murdoch, L and Czerniak, A and Meloni, I and Renieri, A and Kinali, M and Mazarakis, ND},
doi = {brain/awaa028},
journal = {Brain: a journal of neurology},
pages = {811--832},
title = {Gene replacement ameliorates deficits in mouse and human models of cyclin-dependent kinase-like 5 disorder},
url = {http://dx.doi.org/10.1093/brain/awaa028},
volume = {143},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Cyclin-dependent kinase-like 5 disorder is a severe neurodevelopmental disorder caused by mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene. It predominantly affects females who typically present with severe early epileptic encephalopathy, global developmental delay, motor dysfunction, autistic features and sleep disturbances. To develop a gene replacement therapy, we initially characterized the human CDKL5 transcript isoforms expressed in the brain, neuroblastoma cell lines, primary astrocytes and embryonic stem cell-derived cortical interneurons. We found that the isoform 1 and to a lesser extent the isoform 2 were expressed in human brain, and both neuronal and glial cell types. These isoforms were subsequently cloned into recombinant adeno-associated viral (AAV) vector genome and high-titre viral vectors were produced. Intrajugular delivery of green fluorescence protein via AAV vector serotype PHP.B in adult wild-type male mice transduced neurons and astrocytes throughout the brain more efficiently than serotype 9. Cdkl5 knockout male mice treated with isoform 1 via intrajugular injection at age 28–30 days exhibited significant behavioural improvements compared to green fluorescence protein-treated controls (1012 vg per animal, n = 10 per group) with PHP.B vectors. Brain expression of the isoform 1 transgene was more abundant in hindbrain than forebrain and midbrain. Transgene brain expression was sporadic at the cellular level and most prominent in hippocampal neurons and cerebellar Purkinje cells. Correction of postsynaptic density protein 95 cerebellar misexpression, a major fine cerebellar structural abnormality in Cdkl5 knockout mice, was found in regions of high transgene expression within the cerebellum. AAV vector serotype DJ efficiently transduced CDKL5-mutant human induced pluripotent stem cell-derived neural progenitors, which were subsequently differentiated into mature neurons. When treating CDKL5-mutant neuro
AU  - Yunan,Gao Y
AU  - Irvine,E
AU  - Eleftheriadou,I
AU  - Naranjo,CJ
AU  - Hearn-Yeats,F
AU  - Bosch,L
AU  - Glegola,J
AU  - Murdoch,L
AU  - Czerniak,A
AU  - Meloni,I
AU  - Renieri,A
AU  - Kinali,M
AU  - Mazarakis,ND
DO  - brain/awaa028
EP  - 832
PY  - 2020///
SN  - 0006-8950
SP  - 811
TI  - Gene replacement ameliorates deficits in mouse and human models of cyclin-dependent kinase-like 5 disorder
T2  - Brain: a journal of neurology
UR  - http://dx.doi.org/10.1093/brain/awaa028
UR  - https://academic.oup.com/brain/article/143/3/811/5775569
UR  - http://hdl.handle.net/10044/1/77254
VL  - 143
ER  -
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