The University of Sheffield
The Medical School

Professor Mimoun Azzouz

Professor of Translational Neuroscience

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

Telephone: +44 (0)114 2222238
Email: m.azzouz@sheffield.ac.uk

Name of Secretary: Rebecca Brown
Telephone: +44 (0)114 2222261
Email: rebecca.brown@sheffield.ac.uk

Education & Training

Professional Activities

Collaborations

Research

My group has a long-standing interest in developing gene therapy approaches for neurodegenerative disease. The newly established team utilises viral based gene transfer systems both for research and gene therapy applications. Such viral systems have included lentiviruses and adeno-associated vectors. Our research focuses on developing new therapeutic strategies for motor neuron diseases (ALS and SMA) and Parkinson´s disease. We also collaborate with other groups looking at new experimental approaches to treatment of Alzheimer´s disease and multiple sclerosis. Members of the team are also investigating molecular pathways and signaling of motor neuron death associated with ALS and SMA.

Recent significant achievement of the team includes generation of scAAV encoding a codon-optimized version of the SMN1 complementary DNA (cDNA) and used it to enhance SMN protein expression more effectively than previously achieved in the murine spinal cord. The team demonstrate that a single intravenous (i.v.) injection of scAAV9-coSMN (codon-optimized SMN) rescues the lethal phenotype in the well established animal model of SMA, SMNΔ7. The treatment led to a robust increase in survival of the SMNΔ7 mice after systemic delivery of scAAV9-coSMN. Survival analysis revealed that 80% of scAAV9-coSMN–treated animals showed robust extension in the life-span (with a maximal survival of >200 days

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This pre-clinical proof-of-concept has generated great optimism for SMA therapy. The current strategy provides four major competitive advantages: i) The new scAAV allows efficient BBB crossing and gene transfer into motor neurons. These vectors have shown high efficacy for SMN replacement treatment of an SMA mouse model. ii) The advantage of using scAAV over traditional single-stranded DNA AAV is that it allows a faster expression of the transgene in vivo. iii) SMN replacement is the most attractive therapy for SMA since we are trying to tackle the causative factor in SMA. iv) Finally, we uniquely use a codon optimised SMN gene to enhance protein expression. This should allow us to use less viral vector for a potential clinical trial in human patients. This key proof-of-principle experiment has prompted the team to progress this strategy towards obtaining a Biologic License Application to initiate a phase I clinical trial in SMA patients.

Principal Funding Sources

Members of Research Group

Selected publications

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, In press.

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). Abstract: Reprint: Full Text:

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).