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Dr Azadeh Khalili-Shirazi
Queen Square
London
WC1 3BG
Tel: 0207 676 2180
Appointment
  • Principal Research Fellow
  • MRC Prion Unit at UCL
  • UCL Institute of Prion Diseases
  • Faculty of Brain Sciences
Research Groups
Research Themes
Research Summary

Prion diseases like variant Creutzfeldt-Jakob disease (vCJD) in humans and BSE in cattle are fatal brain diseases caused by an infectious agent, known as a prion. Prions are thought to be composed of abnormal forms (PrPSc) of a protein, which is a normal constituent of brain cells cellular prion protein (PrPC). These disease-associated forms of prion protein form clumps or plaques in the brain and this process causes damage to, and then loss of, brain cells.

In vCJD, prions first infect lymphoreticular tissues outside the brain and then spread to the brain and cause damage leading to symptoms of the disease. Since these abnormal prion proteins are formed from one of the body’s own proteins, they are not recognised as being foreign by the immune system , which normally tends to produce antibodies and protect against infection. This “immune tolerance” means there is a lack of natural defence against prion infection.

In addition to ingestion of BSE-contaminated food products, it is thought that vCJD may be transmitted by contaminated surgical instruments and it is now known that it can be spread through blood transfusion or treatment with blood products that were derived from a donor who was incubating vCJD. It is unknown at present how many healthy people may be infected with vCJD prions. Several thousand people in the UK have been notified that they are at increased risk of developing CJD because of exposure to blood, blood products or surgical instruments that may have been contaminated.

We have used prion proteins to produce a large range of monoclonal antibodies (mAb) that recognise native PrPC and PrPSc from many species and are very effective in curing prion-infected cells. Two mAbs have been shown to be protective against prion disease in mice, preventing PrPSc accumulation and delaying onset of prion disease. The blood-brain-barrier limits the entry of large molecules such as antibodies into the brain from the circulation, and so to investigate the therapeutic potential of these mAbs against neurodegeneration, we are investigating methods for them to gain entry into the brain where they may be effective in treating the disease. The mAbs are thought to work by binding to PrPC and preventing its conversion into PrPSc. We are studying the relationship between the immune system and the normal (PrPC) and diseased (PrPSc) forms of prion protein, in the hope of developing a mAb treatment with minimal side effects.

The MRC Unit has been funded by MRC to “humanise” two of these mice mAbs with a view to their trial in human, to see if they may be useful to treat prion infection and disease. The therapeutic molecular interaction between one of these mAbs (ICSM18) and prion protein has been characterised by X-ray crystallography, and the mAb humanised. The preclinical translational work is well underway, as are parallel studies to better understand the mAb and study potential side effects. Currently, many mAbs are used in clinical trials in the treatment of various diseases, such as cancer, rheumatoid arthritis, multiple sclerosis and Alzheimer's disease.

Academic Background
1988 PhD Doctor of Philosophy – Immunology University of London
1981 M.Phil Master of Philosophy – Medicine University of London
1977 BSc Bachelor of Science – Comparative Physiology Queen Mary and Westfield College
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