Title:Therapy in Prion Diseases
VOLUME: 13 ISSUE: 19
Author(s):Gianluigi Forloni, Vladimiro Artuso, Ignazio Roiter, Michela Morbin and Fabrizio Tagliavini
Affiliation:IRCCS Istituto di Ricerche Farmacologiche "Mario Negri" Via La Masa 19, 20156 Milano, Italy
Keywords:Clinical trials, immunotherapy, presymtomatic treatment, prion diseases, prion protein, oligomers, therapeutic targets.
Abstract:In the last two decades, knowledge of the neurobiology of prion diseases or transmissible spongiform encephalopathies
(TSE) has significantly advanced, but a successful therapy to stop or delay the progression of these disorders
remains one of the most challenging goals of biomedical research. Several obstacles to this achievement are in common
with other neurodegenerative disorders: difficulties to move from experimental level to clinical stage; appropriate timing
of intervention; correct set up of clinical trial. Also in terms of molecular bases of disease, TSE and the other neurodegenerative
disorders associated with protein misfolding such as Alzheimer, Parkinson and Huntington diseases, share a central
pathogenic role of soluble small aggregates, named oligomers, considered the culprit of neuronal dysfunction: accordingly,
these disorders could by termed oligomeropathies. However, the rapid progression of TSE, together with their
clinical and molecular heterogeneity, make the therapeutic approach particularly problematic. The main target of the antiprion
strategy has been the pathological form of the cellular prion protein (PrPC) termed PrPSc, invariably associated with
the diseases. Several compounds have been found to affect PrPSc formation or enhance its clearance in in vitro models,
and prolong survival in experimental animals. However, few of them such as quinacrine and pentosan polysulfate have
reached the clinical evaluation; more recently, we have conducted a clinical trial with doxycycline in patients with
Creutzfeldt-Jakob disease without satisfactory results. In experimental conditions, active and passive immunization with
antibodies against PrP and mucosal vaccination have shown to protect from peripheral infection. Other studies have proposed
new potentially effective molecules targeting PrP oligomers. Furthermore, the possibility to interfere with PrPC to
PrPSc conversion by an active control of PrPC is another interesting approach emerging from experimental studies. However,
in common with the other oligomeropathies, early diagnosis allowing to treat at risk population in a preclinical stage
represent the more realistic perspective for efficient TSE therapy.
