Title: Transmission studies in humanised transgenic mice to investigate recent MV vCJD case
Funder: Department of Health and Social Care

Abstract: Background Bovine spongiform encephalopathy (BSE) prions infected humans causing variant Creutzfeldt-Jakob disease (vCJD). Historically all definite diagnoses have been in patients with a particular prion protein (PrP) genotype (MM) at polymorphic codon 129, where either methionine (M) or valine (V) is encoded. Recently however we identified the first definite vCJD patient with an MV genotype. This patient had pathognomonic neuropathology and molecular strain type but a clinical presentation and other features more typical of sporadic CJD. Autopsy tissues from this patient have been consented for research and now provide the opportunity to study the tissue distribution of infectivity and the strain properties of prions propagated in MV vCJD in comparison with MM vCJD and other forms of human prion disease. Aim To determine the transmission properties of MV vCJD and compare with our existing data for MM vCJD and other forms of human prion disease. Research plan and methods of investigation We will prepare brain and lymphoreticular tissue isolates from the MV vCJD patient and inoculate these into well characterised lines of transgenic mice expressing human PrP and wild type mice followed by detailed molecular and neuropathological analyses of brain to perform biological and molecular prion strain typing. These data will be compared with a completed historical transmission series of more than fifty isolates of other forms of human prion disease to the same mice. Through these experiments we will determine whether there is co-propagation of sporadic CJD-like or novel prions strains together with vCJD prions in the MV patient and inform on whether MV vCJD has a peripheral pathogenesis (and levels of infectivity outside the CNS) similar to MM vCJD. These findings will be of considerable interest with respect to whether anonymous screening of surgical appendix tissue may have detected subclinical vCJD infection in 129 MV individuals and whether MV vCJD subclinical carriers may pose additional risks for secondary transmission of human prions through iatrogenic routes. Research team The proposed research will be conducted within the MRC Prion Unit at UCL and led by Dr Jonathan Wadsworth and Professor John Collinge. The Unit is internationally recognised for its expertise in prion transmission studies and is equipped with specialised facilities at microbiological containment level 3 to safely handle human and zoonotic prion pathogens. Potential impact on relevant policy This research is directly tailored to the Department of Health s priority research call on vCJD and specifically seeks to understand the natural course of vCJD infection, including variation in host/agent interaction. Work undertaken in this proposal will provide a better understanding of the nature and extent of BSE-related prion disease in the UK and we anticipate that our findings will assist future policy guidance designed to minimize the risk of transmitting human prions via iatrogenic routes.

Lay abstract: Prions, the infectious agents causing BSE in cows and variant CJD (vCJD) in humans are unique in medical research. Unlike all other infectious agents (bacteria and viruses) the infectious particle does not contain genetic information (genes) but instead consists of a misshapen form of one of the body s own proteins. Although prions do not carry genetic material they come in several different forms, called prion strains that cause different forms of the disease. Our research aims to understand the fundamental biology of what makes prion strains different from one another and why some are able to cross from animals to humans to cause disease. For these studies we use genetically altered mice (transgenic mice) to understand which animal prion strains may pose a risk to humans and to see what these diseases may look like should people become infected. These studies confirmed that vCJD is caused by the same prion strain that causes BSE in cows and have established that a person s genetic makeup may influence the type of prion disease they will develop if infected with BSE prions. Because of the very long time periods possible between infection and the appearance of symptoms the number of people with BSE infection is unknown. This has raised fears that infected people who have no signs of the disease might pass it on to others by surgery, blood transfusion and other medical routes. Very recently we have seen a patient with vCJD who has a genetic makeup that is different from all other vCJD patients. We now want to study the prions from this patient using transgenic mice to see whether the properties of the prions have changed and whether these could pose any new risks. This research will help us to better understand BSE-related prion diseases in the UK and this knowledge will help the government to take the right steps to protect public health.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL