"My team seek to understand what causes amyotrophic lateral sclerosis - also known as motor neuron disease - and fronto-temporal dementia with the aim of finding more effective therapies. " Chris Shaw
UK DRI Group Leader
A world-leader in the genetics of neurodegenerative diseases, Chris Shaw is Professor of Neurology & Neurogenetics at the IoPPN and Director of The Maurice Wohl Clinical Neuroscience Institute at Kings College London. After studying medicine in New Zealand, Chris did his doctoral training at the University of Cambridge as a Wellcome Fellow. A pioneer in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), since 2008 his group has discovered four new risk genes for ALS, and his work was recognised in 2019 with a Kea World Class New Zealand Award. Prof Shaw oversees an ambitious programme investigating proteostatic mechanisms and developing gene therapies for ALS and FTD. in 2021, he co-founded the UK DRI spin-out company Aviadobio to develop gene therapy treatments for FTD and ALS.
1. At a glance
Special delivery: Correcting faulty genes in neurodegenerative disease
Amyotrophic lateral sclerosis (ALS, also known as motor neurone disease (MND)) and frontotemporal dementia (FTD) are two examples of devastating neurodegenerative disease. While not all symptoms are shared between the two diseases (ALS primarily affecting movement, FTD primarily affecting behaviour and personality), there is significant overlap in their genetic causes and underlying biology.
Prof Chris Shaw is studying FTD and ALS to advance our understanding of their molecular causes and to develop effective new targeted treatments.
A key goal is to develop an innovative new gene therapy for people with a type of FTD caused by faults in a specific gene. The approach involves delivering the correct copy of the gene into their body. If laboratory tests show promising results, Prof Shaw plans to test the effectiveness of this potential new treatment in a human clinical trial. The team are also setting up a facility to support other researchers across the UK DRI to develop other exciting new gene therapies.
Other work of Chris and his group involves investigating how the build-up of a protein called TDP-43 inside neurons contributes to ALS and FTD, to identify effective new treatments that can help prevent these toxic aggregates forming and/or enhance their clearance from the brain.
2. Scientific goals
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two closely related neurodegenerative conditions with significant overlap in clinical, pathological, radiological, and genetic characteristics; an intronic GGGGCC repeat expansion in C9orf72 is the most common genetic cause of both disorders. Prof Chris Shaw is studying FTD and ALS to advance our understanding of their molecular causes and to develop effective new targeted treatments.
Chris and his team are initiating a new gene therapy programme as part of his UK DRI programme, based on the development of adeno-associated viral (AAV) vectors capable of delivering safe, long-lasting and cost-effective gene therapies for neurodegenerative disorders in appropriately selected patient populations. Although several trials of intrathecal antisense oligonucleotides therapies in a range of neurodegenerative disorders are currently underway, no trials have yet been conducted using AAV vectors. Thus, crucial preclinical experiments could pave the way to first-in-human experimental medicine studies with the potential to carve a path for the development of many more AAV vector delivered therapies in neurodegeneration.
Alongside the development of novel gene therapy approaches, the team is also investigating TDP-43 aggregates, which are the hallmark pathology in 95% of all ALS and tau-negative FTD cases. TDP-43 is a DNA and RNA binding protein that regulates RNA transcription, splicing, trafficking and translation. The group plan to map the earliest molecular events that promote TDP-43 mislocalisation and aggregation as well as endogenous proteostatic neuroprotective response in patient iPSC-derived neurons carrying a range of proteostatic gene defects, and TDP-43 transgenic mice. Key degenerative and protective signatures will be validated in human post-mortem tissues. Armed with a greater understanding of the factors that promote TDP-43 aggregation and regulate its clearance, they will seek to manipulate these pathways using gene knockdown/overexpression and small molecules in order to develop a rational therapeutic strategy aimed at preventing aggregation and enhancing endogenous proteostasis.
Main objectives and research goals:
1. To develop novel AAV-based gene therapy therapeutic approaches. Optimising AAV9 vectors for gene delivery into the CNS from preclinical experiments in cells and rodents up to first-in-human experimental medicine studies.
2. To map TDP-43 proteostasis in vitro using human iPSc-derived neurons: Phenotypic analyses including transcriptomics, proteomics and high-content imaging in cultured motor neurons – including patient-derived iPSC and isogenic lines generated by genome editing with CRISPR/Cas9.
3. Team members
Dr Neda Ali Mohammadi Nafchi (Postdoctoral Researcher)
Dr James Bashford (Postdoctoral Researcher)
Dr Olivier Brock (Postdoctoral Researcher)
Dr Mark Crook-Rumsey (Postdoctoral Researcher)
Dr Bibiana Mota (Postdoctoral Researcher)
Dr Andrea Perera (Postdoctoral Researcher)
Dr Younbok Lee (Research Assistant)
Joseph Allison (Research Assistant)
McQuinn Gumus (Research Assistant)
Afra Aabadien (PhD Student)
Emily Annuario (PhD Student)
Judith Bilgorai (PhD Student)
Anna Carobin (PhD Student)
Shiden Solomon (PhD Student)
Aleksandra Kaliszewska (Scientific Support Staff)
Within UK DRI:
- Dr Jonathan Rohrer, UK DRI at UCL
Frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), AAV gene therapy, human iPS neurons, TDP-43
AAV design, proteomics, transcriptomics, high-content imaging, CRISPR/Cas9, human iPSC-derived neuronal culture
7. Key publications
Smith BN, Topp SD, Fallini C, Shibata H, Chen HJ, Troakes C, King A, Ticozzi N, Kenna KP, Soragia-Gkazi A, Miller JW, Sato A, Dias DM, Jeon M, Vance C, Wong CH, de Majo M, Kattuah W, Mitchell JC, Scotter EL, Parkin NW, Sapp PC, Nolan M, Nestor PJ, Simpson M, Weale M, Lek M, Baas F, Vianney de Jong JM, Ten Asbroek ALMA, Redondo AG, Esteban-Perez J, Tiloca C, Verde F, Duga S, Leigh N, Pall H, Morrison KE, Al-Chalabi A, Shaw PJ, Kirby J, Turner MR, Talbot K, Hardiman O, Glass JD, De Belleroche J, Maki M, Moss SE, Miller C, Gellera C, Ratti A, Al-Sarraj S, Brown RH Jr, Silani V, Landers JE, Shaw CE. Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis. Sci Transl Med. 2017: 3;9(388)
Lee YB, Baskaran P, Gomez-Deza J, Chen HJ, Nishimura AL, Smith BN, Troakes C, Adachi Y, Stepto A, Petrucelli L, Gallo JM, Hirth F, Rogelj B, Guthrie S, Shaw CE. C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity. Hum Mol Genet. 2017; 26:4765-4777
Selvaraj BT, Livesey MR, Zhao C, Gregory JM, James OT, Cleary EM, Chouhan AK, Gane AB, Perkins EM, Dando O, Lillico SG, Lee YB, Nishimura AL, Poreci U, Thankamony S, Pray M, Vasistha NA, Magnani D, Borooah S, Burr K, Story D, McCampbell A, Shaw CE, Kind PC, Aitman TJ, Whitelaw CBA, Wilmut I, Smith C, Miles GB, Hardingham GE, Wyllie DJA, Chandran S. C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity. Nat Commun. 2018; 24;9(1):347
de Majo M, Topp SD, Smith BN, Nishimura AL, Chen HJ, Gkazi AS, Miller J, Wong CH, Vance C, Baas F, Ten Asbroek ALMA, Kenna KP, Ticozzi N, Redondo AG, Esteban-Perez J, Tiloca C, Verde F, Duga S, Morrison KE, Shaw PJ, Kirby J, Turner MR, Talbot K, Hardiman O, Glass JD, de Belleroche J, Gellera C, Ratti A, Al-Chalabi A, Brown RH, Silani V, Landers JE, Shaw CE. ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function. Neurobiol Aging. 2018 Nov;71:266.e1-266.e10
Gkazi SA, Troakes C, Topp S, Miller JW, Vance CA, Sreedharan J, Al-Chalabi A, Kirby J, Shaw PJ, Al-Sarraj S, King A, Smith BN, Shaw CE. Striking phenotypic variation in a family with the P506S UBQLN2 mutation including amyotrophic lateral sclerosis, spastic paraplegia, and frontotemporal dementia. Neurobiol Aging. 2019 Jan;73:229.e5-229.e9