Sheffield Institute for
Translational Neuroscience

Professor Mimoun Azzouz

Chair of Translational Neuroscience

ERC Advanced Fellow

Director of Research & Innovation

 


Research Interests

Professor Azzouz has achieved international pre-eminence in the field of gene therapy applications and vector development for neurodegenerative diseases.  His contribution has been outstanding over the last 15 years as evidenced by the quality of publications achieved (see publications list). He has achieved a very high international status in an important field. His original and pioneering work, which has already produced major breakthroughs in animal models of neurodegenerative diseases, will in the near future, translate into major therapeutic advances in the field of human neurodegenerative disease. Azzouz has great drive and passion to employ his scientific skills for the ultimate benefit of patients and families suffering from some of the most devastating diseases in medicine.

Azzouz achievements went beyond therapy development. Indeed, he also made significant discoveries related to the mechanisms of diseases in ALS/MND and SMA. For example, The recent discovery of the mechanism underpinning genome instability and neural cell death caused by C9orf72 expansion in ALS[Nature Neuroscience 20(9):1225-1235. (2017)] and role of PTEN in ALS and SMA [Human Molecular Genetics, 19(16):3159-68 (2010); Brain, 134(Pt 2):506-17 (2011)]. His exceptional achievements were recently recognized at the European level by winning the prestigious ERC Advanced Investigator and ERC PoC Awards designed for individuals with excellence in scientific research. These awards offer him a platform to cement his European leadership in the field of gene therapy and translational neuroscience. 

 

 

Current Projects

  • Utilisation of viral based gene transfer systems for research and therapy applications.
  • Design and development of CNS targeted gene therapy vector systems
  • In vitro and in vivo modelling of ALS/MND and SMA using viral vectors
  • Identification of novel gene therapeutics to neurodegeneration in motor neuron diseases and HSP.
  • Development and testing of various gene therapy concepts: neuroprotection (GDNF, VEGF), gene silencing (SOD1), gene replacement (SMN) and approaches based on CRISPR modulation of expansions (C9orf72).
  • Clinical development to gene therapeutics: GLP regulatory safety studies and GMP manufacturing
  • Biology of RNA binding proteins (e.g. SMN, Gle1).
  • Elucidation of the molecular mechanisms linked to DNA instability in ALS/MND, SMA and Dementia.
  • Molecular pathways and signalling of motor neuron death (e.g. PTEN)

Principal Funding Sources

  • European Research Council (ERC Advanced Investigators Award)
  • Muscular Dystrophy Association (MDA), USA
  • Jennifer Trust for SMA, UK
  • MRC
  • Wellcome Trust
  • FightSMA, USA
  • AFM, France
  • NHS Trust
  • MS Society
  • SMA Europe/SMA Trust
  • EPSRC

Collaborations

  • Professor Pamela Shaw, The University of Sheffield, Sheffield, UK
  • Professor Michael Sendtner, Germany
  • Professor Nicola Woodroofe, Sheffield Hallam University, Sheffield, UK
  • Dr Jean-Marc Gallo, King's College London, UK
  • Dr. Guiseppe Battaglia, The University of Sheffield, UK
  • Professor Ruth Luthi-Carter, University of Leicester
  • Professor Tom Gillingwater, Edinburgh University

Research Team

  • Eva Karyka
  • Joseph Scarrott
  • Emily Graves
  • João Alves-Cruzeiro
  • Louise Whiteley
  • Michela Pulix

Publications

Selected publications

Professor Azzouz has an excellent publication track record. He published papers in high profile and prestigious journals such as Nature, Nature Medicine, Nature Neuroscience, Science Translational Medicine.

Chandran JS, Sharp PS, Karyka E, Aves-Cruzeiro JMDC, Coldicott I, Castelli L, Hautbergue G, Collins MO, Azzouz M. Site specific modification of AAV9 enables both fluorescent imaging of viral particles and identification of the capsid interactome. Scientific Reports 7(1):14766. (2017) doi: 10.1038/s41598-017-15255-2

 

Walker C, Herranz-Martin S, Karyka E, Liao C, Lewis K, Lukashchuk V, Chiang S-C, Ray S, Mulcahy PJ, Jurga M, Tsagakis I, Iannitti T, Chandran J, Higginbottom A, Shaw PJ, Hautbergue GM, Azzouz M*, El-Khamisy SF*. C9orf72 Expansion Disrupts ATM-mediated Chromosomal Break Repair. Nature Neuroscience 20(9):1225-1235. (2017) doi: 10.1038/nn.4604. (*Joint Senior Authors, corresponding author)

 

Hautbergue G, Castelli LM, Ferraiuolo L, Sanchez-Martinez A, Cooper-Knock J, Higginbottom A, Lin Y-H, Bauer CS, Dodd J, Myszczynska MA, Garneret P, Chandran JS, Karyka E, Stopford MJ, Smith EF, Kirby J, Meyer K, Kaspar BK, Isaacs A, De Vos KJ, Ning K, Azzouz M, Whitworth AJ& Shaw PJ. SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficit. Nature Communications, 8:16063. (2017) doi: 10.1038/ncomms16063

 

Herranz-Martin S, Chandran J, Lewis K, Mulcahy P, Higginbottom A, Walker C, Valenzuela IMY, Jones RA, Coldicott I, Iannitti T, Akaaboune M, El-Khamisy SF, Gillingwater TH, Shaw PJ*, Azzouz M*. Viral delivery of C9ORF72 hexanucleotide repeat expansions in mice lead to repeat length dependent neuropathology and behavioral deficits. Dis Model Mech. 10(7):859-868. (2017) doi: 10.1242/dmm.029892

 

Powis RA, Karyka E, Boyd P, Côme J, Jones RA, Zheng Y, Szunyogova E, Groen EJN, Hunter G, Thomson D, Wishart TM, Becker CG, Parson SH, Martinat C, Azzouz M, Gillingwater TH. Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy. JCI Insight 1(11):e87908. (2016)

 

Lukashchuk V., Lewis K.E., Coldicott I., Grierson A.J., Azzouz M. AAV9-mediated central nervous system-targeted gene delivery via cisterna magna route in mice. Mol Ther Methods Clin Dev. 17;3:15055. (2016).doi: 10.1038/mtm.2015.55.

 

Javed H, Menon SA, Al-Mansoori KM, Al-Wandi M, Majbour NK, Ardah MT, Varghese S, Vaikath NN, Haque ME, Azzouz M, El-Agnaf OM. Development of non-viral vectors targeting the brain as a therapy for Parkinson’s Disease and other brain disorders. Mol Ther. 24(4):746-58. (2016) doi: 10.1038/mt.2015.232.

 


Nanou N, Higginbottom A, Valori C.F., Wyles M., Ning K., Shaw P, Azzouz M. Viral delivery of antioxidant genes as a therapeutic strategy in experimental models of amyotrophic lateral sclerosis. Molecular Therapy 21(8):1486-96. (2013) doi: 10.1038/mt.2013.115.


Kirby J., Ning K., Ferraiuolo L., Heath P.R., Ismail A., Kuo S-W., Cox L., Sharrack B., Wharton S.B., Ince P.G., Shaw PJ., Azzouz M. PTEN/Akt pathway linked to motor neuron survival in human SOD1-related amyotrophic lateral sclerosis. Brain, 134(Pt 2):506-17 (2011).


C. F. Valori, K. Ning, M. Wyles, R. J. Mead, A. J. Grierson, P. J. Shaw, M. Azzouz, Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy . Sci.Transl. Med. 2, 35ra42 (2010).


Ning K, Drepper C, Valori C, Wyles M, Higginbottom A, Shaw P, Azzouz M*, Sendtner M*. PTEN depletion rescues axonal growth defect and improve survival in SMN-deficient motor neurons. Human Molecular Genetics, 19 (16):3159-68 (2010)(* joint senior authors).


Jarraya B, Drouot X, Brouillet E, Condé F, Azzouz M, Kingsman SM, Hantraye P, Mazarakis ND & Palfi S. Dopamine Gene Therapy for Parkinson´s Disease in a Nonhuman Primate Without Associated Dyskinesia. Sci. Transl Med. 1 (2):2ra4. (2009)


Wong LF,. Yip PK, Battaglia A, Grist J, Corcoran J, Maden M, Azzouz M, Kingsman SM, Kingsman AJ, Mazarakis ND and McMahon SB. Retinoic acid receptor β 2 promotes functional regeneration of sensory axons into the adult rat spinal cord. Nature Neuroscience, 9(2):243-250 (2006)


Ralph GS, Radcliffe PA, Bilsland L, Leroux MA, Greensmith L, Mitrophanous KA, Kingsman SM, Mazarakis ND, & Azzouz M Silencing of mutant SOD1 using interfering RNA induces long term reversal of ALS in a transgenic mouse model. Nature Medicine, 11(4):429-33 (2005)


Ralph GS, Mazarakis ND & Azzouz M. Therapeutic gene silencing in neurodegenerative disease using interfering RNA. Journal of Molecular Medicine, 83(6):413-9 (2005)


Teng Q, Garrity-Moses M, Tanase D, Liu JK, Mazarakis ND, Azzouz M, & Boulis NM. Trophic activity of rabies G protein pseudotyped EIAV mediated IGF-I motor neuron gene transfer in vitro. Neurobiology of Disease, 20: 694-700 (2005)


Dowd E, Monville C, Torres E, Azzouz M, Mazarakis ND, Dunnett SB. The neurotrophic capabilty of letivector-mediated expression of GDNF: funtional assessment using a complex operant lateralised nose-poking task. EJN, 22: 2587-2595 (2005)


Azzouz M, Ralph GS , Storkebaum E, Walmsley L, Mitrophanous KA, Kingsman SM, Carmeliet P, & Mazarakis ND. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature, 429: 413-417 (2004).


Azzouz M, Le T, Walmsley L., Monani U., Wilkes F, Mitrophanous KA, Kingsman SM, Burghes A, & Mazarakis ND. LentiVector-Mediated SMN Replacement in a Mouse Model of spinal Muscular Atrophy. The Journal Clinical Investigation 114: 1726-1731 (2004).


Azzouz M, Martin-Rendon E, Barber RD, Mitrophanous KA, Carter EE, Rohll JB, Kingsman SM, Kingsman AJ, and Mazarakis ND. Multicistronic Lentiviral Vector-Mediated Striatal Gene Transfer of Aromatic L-Amino Acid Decarboxylase, Tyrosine Hydroxylase and GTP Cyclohydrolase I Induces Sustained Transgene Expression, Dopamine Production and Functional Improvement in a Rat Model of Parkinson´s Disease. The Journal of Neuroscience 22:10302-10312 (2002).


Mazarakis ND, Azzouz M, Rohll JB, Ellard FM, Olsen A , Carter EE, Barber R, O´Malley K, Kingsman SM, AJ Kingsman, and Mitrophanous KA. Rabies-G envelope pseudotyping of lentiviral vectors enables retrograde axonal transport and access to the nervous system after peripheral delivery. Human Molecular Genetics 10: 2109-2121 (2001).


Azzouz M, Hottinger A, Zurn A, Aebischer P, and Bueler H. Increased motoneuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding Bcl-2. Human Molecular Genetics 9: 801-811 (2000).

Professional Activities

  • 2006-08 Advisor for Oxford BioMedica plc.
  • 2008-13 Member of the Scientific Advisory Board, Muscular Dystrophy Association (F)
  • 2010 Committee of assessors for Genethon, Paris, France
  • 2010-16 Member of Strategic Board, AFM (F)
  • 2011-12 Advisor for BioMarin Pharmaceutical Inc
  • 2012-14 Panel Member for the Research Council of Norway
  • 2012-16      Panel member for the UK Medical Research Council (DPFS, MRC)
  • 2012-13 Advisor for QBRI, Qatar Foundation, Qatar
  • 2012-  Member of Research Excellence Framework 2014 (REF14) Committee, FMDH
  • 2013-14      Neuroscience Panel Member, German Ministry of Education and Research
  • 2013-  Panel member, Health Research Board (HRB), Dublin (Ireland)
  • 2014-  Wellcome Trust Virtual Panel member for Translational Research Funds
  • 2015-17 Advisor for Spherium biomed
  • 2016- Board member of British Society for Gene & Cell Therapy
  • 2017- Advisory Board, IBRO-MENA
  • 2017- Scientific Advisor for the Batten CLN7 trial (Beat Batten)
  • 2017- Scientific Advisor for CureSPG47
  • 2017- Assessor for Innovate UK
  • 2017- Scientific Advisory Board, Telocyte, USA

Biography

Biography

Jan 2006-present
University of Sheffield
Chair of Translational Neuroscience

2003 – 2005
Oxford Biomedica Ltd, Oxford
Director of Neurobiology

2000 – 2003
Oxford Biomedica Ltd, Oxford
Senior Scientist

1997 - 2000
Gene Therapy Centre, Lausanne, Switzerland
Postdoctoral Position

1993 - 1997
University Louis Pasteur of Strasbourg, France
Ph.D. in Neuropharmacology

Awards

Honors & Awards

2017:    ERC Proof-of-Concept Award

2014:    Chair and organiser of Fusion Conference, Cancun, Mexico

2012:    ERC Advanced Investigator Award

2012:    Nomination for The Shaw Prize 2012

2011:    MRC DPFS Award holder

2008:    Chairman of UK SMA Conference

2006:    Faculty of the American Society of Gene Therapy

2006:    Faculty of the American Society of Neuroscience

2006:    Approached for an advisory role to the UK Government Department for Environment, Food and Rural Affairs (DEFRA) for “Defra desk study to review environmental risks from research trials and marketing of Genetically Modified (GM) veterinary and human medicines”. 

Contact Details

Academic Neurology Unit
Department of Neuroscience
SITraN
University of Sheffield
Room B31
385a Glossop Road
Sheffield
S10 2HQ

T: +44 (0)114 2222238
E: m.azzouz@sheffield.ac.uk

Secretary: Bev Carter 
Telephone: +44 (0) 114 2222295
Email: bev.carter@sheffield.ac.uk