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Using genome engineering technologies in mice, we aim to understand the molecular and phenotypic nature of prion strains as well as provide models for evaluating candidate small molecule and antibody therapeutics, which we anticipate will have relevance for treating other neurodegenerative diseases. Modelling inherited prion disease, caused by genetic mutations in the gene encoding the prion protein, constitutes 10-15% human prion disease cases, and provides an opportunity to model and study diverse strain types and characteristics that may illuminate wider mechanisms of prion biology, and wider mechanisms of neurodegeneration. We generate and study transgenic and knock-in humanised models in order to maintain authentic human strain characteristics that have been proven to be distinct from prions derived from other mammalian species.
Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models.
Devoy A, Price G, De Giorgio F, Bunton-Stasyshyn R, Thompson D, Gasco S, Allan A, Codner GF, Nair RR, Tibbit C, McLeod R, Ali Z, Noda J, Marrero-Gagliardi A, Brito-Armas JM, Williams C, Ozturk M, Simon M, O’Neill E, Harrison J, Atkins G, Corrochano S, Stewart M, Gilthorpe JD, Teboul L, Acevedo-Arozena A § , Fisher EMC and Cunningham TJ. iScience. 2021 Nov 15;24(12):103463.
ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity.
Garone MG, Birsa N, Rosito M, Salaris F, Mochi M, de Turris V, Nair RR, Cunningham TJ, Fisher EMC, Morlando M, Fratta P, Rosa A. Commun Biol. 2021 Sep 1;4(1):1025.
Sizing, stabilising, and cloning repeat-expansions for gene targeting constructs.
Nair RR, Tibbit C, Thompson D, McLeod R, Nakhuda A, Simon MM, Baloh RH, Fisher EMC, Isaacs AM, Cunningham TJ.Methods. 2020; Jul 25;S1046-2023(20)30028-1.
NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease.
Maza AM, Jarvis S, Lee WC, Cunningham TJ, Schiavo G, Secrier M, Fratta P, Sleigh JN, Sudre CH, Fisher EMC, Sudre CH. Scientific Reports. 2021;11: 12251. Cunningham TJ, Fisher EMC, Fratta P, Gilthorpe JD. DNA Editing for Amyotrophic Lateral Sclerosis: Leading Off First Base. CRISPR J. 2020; Apr;3(2):75-77.
Humanising the mouse genome piece by piece Zhu F, Nair RR, Fisher EMC§ , Cunningham TJ§ . Nat Commun. 2019;10(1):1845.
Uses for humanised mouse models in precision medicine for neurodegenerative disease.
Nair RR, Corrochano S, Gasco S, Tibbit C, Thompson D, Maduro C, Ali Z, Acevedo-Arozena A, Cunningham TJ§ , Fisher EMC§ . Mamm Genome. 2019;30(7-8):173-191.
TDP-43 mutations increase HNRNP A1-7B through gain of splicing function
Sivakumar P, De Giorgio F, Ule AM, Neeves J, Nair RR, Bentham M, Birsa N, Humphrey J, Plagnol V, Acevedo-Arozena A, Cunningham TJ, Fisher EMC, Fratta P. . Brain. 2018;141(12):e83