Baird, William;
(2019)
Genetic therapy for congenital melanocytic naevi.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
Congenital Melanocytic Naevus (CMN) syndrome is a rare sporadic disease which is characterised by large and/or multiple moles covering up to 80% of an individual’s skin. Patients can have associated congenital neurological abnormalities, and are at risk of melanoma arising in the skin or brain. In 70% of cases the condition is caused by a postzygotic heterozygous missense mutation in the gene NRAS, most commonly NRAS c.(181C>A), p.(Q61K). NRAS encodes a GTPase signal transduction protein that is critical in the control of many key cell functions including regulation of proliferation, differentiation, and apoptosis. Pathogenic mutations in NRAS leading to amino acid changes in codon 61 result in constitutive activation of downstream signalling pathways. There is currently no treatment for CMN syndrome, with surgical removal of CMN having limited cosmetic effect on large or multiple naevi, no treatment available for most neurological abnormalities, and no successful treatment for melanoma in this context. Gene therapy offers the potential for reversing or attenuating the phenotype of CMN. The aim was to correct or attenuate the effects of the NRAS c.(181C>A) mutation in an in vitro cell culture model, in an allele-specific way which allows normal functionality of the wildtype allele. This has been successfully achieved through: i) culture and detailed functional of characterisation of paired NRAS c.(181C>A) mutant and wildtype melanoma cell lines, ii) design and optimisation of allele-specific knockdown of mutant c.(181C>A) NRAS gene expression using siRNA; iii) design and optimisation of mutant c.(181C>A) NRAS-specific CRISPR sgRNA. These results provide the first evidence of a potential genetic therapy for CMN syndrome, and in addition serve as proof of concept for the treatment of other mosaic diseases of the skin.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Genetic therapy for congenital melanocytic naevi |
| Event: | UCL (University College London) |
| Language: | English |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10070630 |
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