NR AORY
AU Dormont,D.
TI Therapeutic strategies for transmissible spongiform encephalopathies
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Oral sessions OS-33
PT Konferenz-Vortrag
AB
Prion diseases, Transmissible spongiform encephalopathies (TSE), are fatal neurodegenerative diseases described in humans and in animals. In animal models, infectivity is always associated with a proportional accumulation of the abnormal issoform of a host-encoded protein, PrP. Differences between normal (PrPc) and abnormal PrP (PrPsc) are probably only at the level of the tri-dimensional structures. At the clinical stage of the disease, brain lesions are mainly composed of neuronal death, gliosis and spongiosis. Pathogenesis differs depending on the prion strain, the route of inoculation and the genetic background of the host. When peripheral exposure occurs it is believed that neuroinvasion is possible through the implication of the immune system and the peripheral nervous system (PNS). Follicular dendritic cells (FDC) play a critical role in neuroimmune interface.
Based on pathogenesis data, any TSE therapeutic strategy: has 1) to prevent of infection at the primary site of replication (mainly immune system and nervous plexuses associated with digestive tract), 2) to prevent of infection of lymphoid organs (especially follicular dendritic cells), 3) to block the neuroimmune interface, 4) to inhibit TSE agent progression in the PNS, 5) to inhibit prion propagation inside the CNS, 6) to inhibit PrP-induced neuronal death and gliosis-induced synthesis of neurotoxic mediators 7) to inhibit PrPc/PrPsc transconformation, and 8) to enhance PrPsc clearance.
There is no experimental model that would permit, today, to grow human TSE agents in vitro. Therefore, drug screening can be done only in some host-strain combinations involving murine TSE adapted agents. In vivo models either are not validated for therapy approaches (i.e. transgenic mice harbouring the PrP gene) or require months of experiments in high-level safety facilities.
Although a large number of drugs have been tested in in vitro experimental models few of them are effective in vivo: polyene antibiotics, dextran sulphate, polyoxometallates, branched polyamines, PrP-derived peptides, ß sheet breakers, porphyrines and phtalocyanines. As a general rule, in vivo efficacy depends upon drug regimen, onset of the treatment with regards to the pathogenesis, prion strain and host. This underlines the absolute need of testing any drug candidate in several host-strain combinations before starting phase II/III trials in humans.
Among the new strategies that have been evaluated recently, immune intervention appears to be promising: antibodies against PrP can cure chronically infected cells in vitro, and some of those antibodies can also prevent disease when administered early after infection by peripheral route. This may give a rationale for vaccination against TSEs in the future.
Nevertheless, at present, one needs to have high output screening methods in experimental models that permit, for example, to evidence molecules that interact with PrP transconformation. Such drugs would then be evaluated in chronically infected cells and in rodent models of TSEs. Other strategies that do not target PrP transconformation, may be directly tested in vivo. Finally, before entering clinical trial, drugs that have not been used in humans before should be evaluated for their toxicity and their efficiency in primates.
AD Dominique Dormont, CEA, Service de Neurovirology CRSSA, EPHE, Fontenay aux Roses cedex, France
SP englisch
PO Deutschland