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British Medical Bulletin 66:281-292 (2003)
© 2003 Oxford University Press

Approaches to prophylaxis and therapy

An investigation into prion disease diversity

Dominique Dormont

Service de Neurovirologie, CEA, CRSSA, EPHE, Univeristé Paris XI, Fontenay-aux-Roses, France


   Abstract
Top
 Footnotes
 Abstract
Scientific background to TSE...
 Models for drug screening
 Experimental TSE therapy
 Immune intervention in TSEs
 Conclusions
 References
 
Despite important progress in experimental treatment of neurodegenerative diseases, no therapeutic strategy has today proven its capability to cure or even to stabilise human TSEs. Pathogenesis experiments performed in rodent TSE models have shown that central nervous system damages are detectable long before the appearance of the clinical symptoms. At the time of disease onset, PrPSc accumulation has almost reached its highest level, and the neuropathological lesions (spongiosis, gliosis) are as intense as they are at the time of death. Therefore, the neurodegeneration that is present at the onset of the disease is beyond therapy, and, in theory, only a preclinical diagnosis of TSEs would permit the prevention (or delay) of neurodegeneration. Unfortunately, there are no diagnostic tests that can be used to show TSE agent infection during the preclinical phase of the disease. Nevertheless, since the appearance of variant Creutzfeldt-Jakob disease (vCJD), those in the scientific community working on experimental therapy have increased their efforts. Tens of drugs have been tested in several experimental models, and there are some high-output screening platforms being used in Europe and in the US. Any rational therapeutic strategy needs to be based on pathogenesis data and/or knowledge on the nature of the causative agent. Therefore, progress in therapy is tightly linked to a better understanding of the basic science of TSE.


   Scientific background to TSE therapy
Top
 Footnotes
 Abstract
 Scientific background to TSE...
Models for drug screening
 Experimental TSE therapy
 Immune intervention in TSEs
 Conclusions
 References
 
Infectivity distribution in TSEs depends on the time point during infection, TSE agent strain, route of inoculation, size of the inoculum and genetic background of the host1Go,2Go. For example, there are large differences in infectivity distribution in peripheral tissue between sporadic CJD and vCJD: infectivity and/or PrPres are detected in spleen, lymph nodes, tonsils and appendix in all cases of vCJD although infectivity is only barely detectable outside the CNS in sporadic and familial CJD3GoGo–5Go. These differences result from different routes of exposure (e.g. it is thought vCJD is likely to be due to BSE agent exposure through food) and differences in intrinsic properties of the two TSE strains. Therefore, one key point for therapy efficacy is the knowledge of the TSE strain that affects a given patient.

In animal models, there are strong differences between peripheral and intracerebral infections. Although infectivity titres reached in the CNS at the end of the clinical disease are comparable for a given host infected with the same agent by different routes, there are important differences in the spread of infectivity from the site of inoculation to the CNS. For example, infectivity is detectable in the CNS only during the second half of the incubation period after intraperitoneal infection6GoGo–8Go. Therefore, peripheral pathogenesis involves at least two mechanisms: (i) those that permit peripheral and chronic replication; and (ii) those that support neuro-invasion. It has now been demonstrated that immune cells play a critical role in peripheral pathogenesis: the immune system is the first site of replication after peripheral exposure. Dendritic cells may be involved in agent transport from the site of infection to the lymphoid organs9Go, and follicular dendritic cells (FDCs) are required for neuro-invasion10Go. PrPSc is mainly found associated with FDCs in infected individuals, and impairing FDC maturation delays neuro-invasion11Go,12Go. It is believed that neuro-invasion occurs due to the proximity of FDCs and sympathetic nerve endings in the lymphoid organs; this proximity permits the entry of TSE agent into the peripheral nervous system (PNS)13Go. The mode of propagation of infectivity in the PNS is still debated, although a requirement for the presence of normal PrP has been demonstrated14Go. Two hypotheses can be formulated: (i) retro-axonal transport of PrPSc; or (ii) infection of Schwann cells15Go. Therefore, peripheral pathogenesis can be summarised as follows:

Pathway 1

This pathway implicate the immune system and includes: (i) infection of immune cells associated with the site of inoculation; (ii) transport of the agent to the lymphoid formations (dendritic cells?); (iii) concentration of PrPSc by mature FDCs (maturation of FDCs depends on B cells); (iv) entry into the PNS; (v) retrograde transport of the agent by the PNS; (vi) entry into the CNS; and (vii) spread of the agent inside the CNS. These pathogenetic mechanisms are probably those in place for vCJD and peripheral iatrogenic contaminations.

Pathway 2

This pathway involves the direct entry of the agent into the nervous cells associated with the digestive track (Meissner and Auerbach plexuses). In this case, neuro-invasion occurs at the time of infection, and the agent enters the CNS through the vagus nerve16Go.

The aetiology of sporadic CJD is unknown. Several authors believe that this disease may result from the spontaneous transformation of the normal PrPC into its abnormal isoform inside the CNS. The low probability of this event would explain the low incidence of sporadic CJD and its appearance at the age of 60–70 years. If this hypothesis is valid, no exposure to any TSE agent is required, and, as a consequence, no pathophysiological mechanism that permits neuro-invasion.

Familial TSEs are associated with a mutation inside the open reading frame of the PrP gene (PRNP). Once again, it is thought that mutated PrP has a higher potential to evolve spontaneously to an abnormal conformation that accumulates inside the CNS. This may explain the earlier age at which familial TSE occurs when compared with sporadic CJD.

Whatever the origin of the contamination and the nature of the agent, numerous data demonstrate the role of PrPSc accumulation in neuronal death and gliosis. For example, PrPSc and PrP-derived peptide 106–126 induce apoptosis of neuronal cells, astrocytic activation and proliferation, and activation of microglial cells. This occurs through diverse mechanisms involving mediators like reactive oxygen radicals (RORs) or inflammation-associated cytokines and chemokines17GoGoGo–20Go. Therefore, preventing PrPSc accumulation would be a key parameter for the efficacy of any TSE therapeutic strategy.

Little is known about the physiological role of PrP in healthy individuals21Go. It is, therefore, difficult to know if TSEs are linked to a loss of function of PrPC or to a gain of function of PrPSc. Nevertheless, there are now indications that PrPSc clearance mechanisms exist. The half life of PrPSc is estimated at ~36 h in infected cells in vitro; in vivo, macrophages can clear both inoculum and neosynthesised PrPSc in an infected individual22Go.

Finally, one should keep in mind that PrPSc accumulation in an affected individual is host-encoded. At present, there are no antibodies that could differentiate PrPC and PrPSc; therefore, any antibody-based strategy should be associated with a break in PrP tolerance.

Based on this pathogenetic information, several therapeutic strategies can be proposed: (i) prevention of infection at the first site of replication; (ii) blockade of TSE agent transport to secondary lymphoid organs; (iii) prevention of FDC infection; (iv) blockade of the neuro-immune interface; (v) inhibition of TSE agent transport by the peripheral nervous system; (vi) inhibition of TSE agent spread in the central nervous system; and (vii) inhibition of neuronal death (neuroprotection).

At the molecular level, this could be achieved by drugs that: (i) inhibit PrPSc/PrPC interactions; (ii) inhibit PrPC/PrPSc transformation; (iii) induce increased PrPSc clearance; or (iv) inhibit neurotoxic mediators that are synthesised in response to PrPSc accumulation.

In theory, several cases can be described:

  1. Treatment of clinical disease or treatment of the preclinical disease after neuro-invasion: compensation of neuronal/glial damages, inhibition of TSE agent replication. Drugs need to cross the blood brain barrier.
  2. Treatment of preclinical disease before neuro-invasion (peripheral exposure): no need to cross blood brain barrier. Drugs should act on immune cells and/or neuro-immune interface.
  3. Prophylaxis of TSEs: this strategy involves the elicitation of an immune response, specific or not, that could block TSE agent replication in peripheral tissues. One of the main challenge of theses strategies is to break the immune tolerance to PrP.


   Models for drug screening
Top
 Footnotes
 Abstract
 Scientific background to TSE...
 Models for drug screening
Experimental TSE therapy
 Immune intervention in TSEs
 Conclusions
 References
 
The evaluation of any drug for its anti-TSE properties requires experimental models – in vitro models (propagation of TSE agents, modulation of neurotoxic mediator production), and in vivo models (animal models of TSEs).

In vitro models

In general, there are no in vivo validated methods for TSE agent detection. Nevertheless, scrapie agent can chronically infect some cells of neuronal origin. Most laboratories use a murine neuroblastoma cell line, N2a, chronically infected with scrapie agent23Go. These experimental models permit screening of any drug that can interfere with PrPSc accumulation (PrPC/PrPSc transformation inhibitors, PrPSc clearance inducers, PrPC synthesis inhibitors). The main limitations of these models are: (i) they are of murine origin and might not be 100% transposable to humans; (ii) only few scrapie strains can be used and the behaviour of an in vitro adapted TSE agent may differ from natural isolates; and (iii) they are restricted to a unique cell population and, therefore, cannot represent physiological interactions between cell populations inside the immune system or the CNS.

Recently, acellular assays for PrPC/PrPSc transformation have been established24Go,25Go. These assays can be used for the evaluation of the molecular target of a given drug that interacts with either PrPC or PrPSc. One of the main limitations is the lack of infectivity of the in vitro transformed PrP.

In vivo models

Due to their ability to cross species barriers, TSE agents can be transmitted to laboratory animals in some experimental situations. The strength of the species barrier is related to the PrP gene sequence homology between donor and recipient. There are several mouse- or hamster-adapted TSE strains that permit calibrated and reproducible infection and disease models. Until now, these models represent the most accurate and the most relevant for the evaluation of drugs. Nevertheless, these models have limitations: (i) they require high-level safety, animal care facilities; (ii) incubation times are in the range of several months; (iii) rodent-adapted TSE strains may not behave as natural strains; and (iv) the physiology of rodents is sometimes very different from human physiology (e.g. intestinal physiology).

Transgenic mice harbouring the human PrP gene in a PrPo/o background are susceptible to both sporadic and familial CJD26Go. Because the number of transgene copies is usually high, these animals, when infected, have relatively short incubation times (50–100 days). The main advantage of these models is the use of a human agent; nevertheless, such models need to be validated before being considered as standards and they are not applicable to vCJD.

Inoculation of primates with CJD agent represents the best model for human TSEs. The primate immune system and CNS are close to those of humans and the use of primates allows pharmacokinetic investigations, behavioural studies, EEG and pathogenesis investigations. Nevertheless, these models require high-cost animal care facilities and primates have incubation times in the range of several years. Moreover, there are justified ethical concerns in the use of primates in biomedical research. As a consequence, these models should be used only in the last stages of the preclinical development of a given drug or vaccine.


   Experimental TSE therapy
Top
 Footnotes
 Abstract
 Scientific background to TSE...
 Models for drug screening
 Experimental TSE therapy
Immune intervention in TSEs
 Conclusions
 References
 
Peripheral infections: immune modulators and antimicrobials

Several drugs that are known to act on the immune system have been tested in animal models. It is believed that the TSE agent has a cell receptor (most probably PrPC), and that PrPC/PrPSc transformation occurs during the internalisation of PrPC through a caveolae-dependent mechanism. Therefore, any process that inhibits TSE agent/receptor interactions would prevent infection. This can be achieved by: (i) specific ligands of PrPSc; (ii) specific ligands of PrPC or its receptor (LRP); and (iii) interactions with the cell membrane that induce biophysical changes incompatible with internalisation processes (e.g. modifications to fluidity or electrostatic charge).

Polyanions
 Polyanions are highly charged molecules that interact with cell membranes. They are known to inhibit entry of several viruses by a non-specific indirect mechanism. Inorganic polyanions (polyoxometallates) and organic polyanions have demonstrated their capacity to delay the onset of clinical disease in animal models. Efficiency requires early administration of polyanions either before or soon after peripheral infection. The efficiency of organic polyanions is correlated with the degree of sulphatation of the drug. In this class of drugs, organic (Dextran sulphate 500, Pentosan sulphate 54), suramine and non-organic polyanions (HPA23) have shown their efficacy in different strain/host combinations27GoGoGo–30Go. With the exception of HPA23, polyanions are efficient only when infection occurs via peripheral routes; this class of drugs is thought to avoid peripheral cell infection and, therefore, to inhibit TSE agent entry into the PNS.

Dapsone is an antibacterial and antiparasitic drug that can cross the blood brain barrier, which has mainly been used for leprosy treatment. In a CJD rodent model, dapsone increases survival by 25% when administered close to the time of experimental infection31Go. These beneficial effects have not been seen in other strain/host combinations32Go.

Follicular dendritic cells as TSE therapeutic strategy targets
 Follicular dendritic cells (FDCs) play an important role in the immune system dependent pathway during peripheral infection. In vivo, these cells accumulate PrPSc in the germinal centres of the secondary lymphoid organs, and they are located close to sympathetic nerve endings. FDCs are involved in the maturation of antigen-specific B-cell clones. This immunological function requires the correct maturation of both FDCs and B-cells. FDC maturation depends upon a molecular dialogue between B-cells and immature FDCs through interaction between lymphotoxin ß and its receptor. Blocking this interaction impairs FDC maturation and, therefore, PrPSc accumulation in the germinal centres and entry of TSE agent into the nervous system11Go,12Go.

Drugs that act on PrPSc: iododoxorubicin, tetracycline, Congo Red, ß-sheet breakers

Several drugs are capable of interaction with PrPSc and intercalation into ß-sheet structures thus allowing a better clearance of PrPSc in vivo.

Iododoxorubicin is an anthracyclin that induces an increase in survival of hamsters when co-inoculated with the 263 K scrapie agent (30% of the placebo-treated infected controls)33Go. This drug cannot cross the blood brain barrier and, therefore, its use in daily practice is not possible.

Because its structural homology with the aglycone moiety of iododoxorubicin and its ability to cross the blood brain barrier, tetracycline has been tested in rodent models. When co-incubated with the inoculum, there are delays in the onset of PrPSc accumulation inside the CNS and the appearance of the clinical symptoms34Go.

Congo Red binds specifically to amyloid structures. In vitro, Congo Red inhibits PrPSc accumulation in chronically infected cells. Its in vivo effects remain controversial: an effect has been seen in some strain/host combinations, although no effect was seen in others35Go,36Go.

Peptides with sequence homology to PrPC and increase in proline content can interact with PrPSc and reverse PrPSc amyloidosis (ß-sheet breakers)37Go. In vitro, peptides derived from PrP115–122 increase PrPSc protease sensitivity and, when co-inoculated with scrapie agent into mice, they can prolong life expectancy significantly.

Molecules that can bind to PrP

Any molecule that binds to proteins can, in theory, modulate PrPC–PrPSc transformation, directly or indirectly (e.g. binding to co-factors or receptors).

PrP has been shown to interact with heparan sulphate proteoglycans (HSPGs) that are present at the cell surface38Go. This interaction could participate in PrPC normal function and/or with multiprotein receptors for PrPSc. For example, HSPGs are required for one of the two interactions between PrP and the precursor of the laminin receptor (LRP)39Go. Some of the HSPG derivatives can cure chronically infected cells in vitro, and preliminary data indicate their ability to decrease PrPSc accumulation in vivo.

Other components belonging to the tertrapyrrol porphyrin and phthalocyanin family can also cure chronically infected cells and increase animal survival when administered during the early phases of peripheral infection with TSE agents.

Increase in PrPSc clearance

Because branched polyamines are thought to stimulate PrPSc proteolysis clearance in endolysosomes, they have been tested in chronically infected cells. A total cure can be obtained in this model; no data have been published on their in vivo efficacy41Go,42Go.

Polyene antibiotics

Polyene antibiotics are antifungal agents derived from amphotericin B. Amphotericin B is thought to interact with ergosterol in the fungal envelope and with cholesterol present in mammalian cell membranes. It is now believed that PrPC is mainly present in cholesterol-rich domains (rafts) in the cell membrane. Therefore, any drug that could interfere with raft biology (modification of chemical composition, physical alteration) could theoretically impair PrPC or PrPC/PrPSc complex endocytosis and thus slow down PrPSc accumulation in treated cells. Amphotericin B and one of its less toxic derivatives, MS 8209, have been evaluated as anti-TSE agents in several host-strain combinations in infected rodents. A significant increase in survival was observed in all combinations tested, particularly for MS 8209 (increase of 100% in survival of infected hamsters)43GoGoGoGoGoGo–49Go. The therapeutic effect could be correlated with a delay in PrPSc accumulation in the brain. Some experimental data50Go indicate that polyene antibiotics could act on the neuro-immune interface and, therefore, slow down neuro-invasion processes.

Another polyene antibiotic, filipin, has also been shown to decrease PrPSc accumulation significantly in chronically infected cells51Go; this effect is associated with a reduction in PrP endocytosis.

Chlorpromazine and quinacrine

One strategy to detect useful drugs is to screen molecules that have been licensed in humans for other indications and that cross the blood brain barrier. Using this approach, Korth and colleagues showed that chlorpromazine and quinacrine can cure infected cells in vitro52Go. Although their efficacy remains to be proven in animal models and in patients, these molecules could be used also as leader molecules, and structural derivatives could be rationally designed and evaluated (e.g. bis-acridine)53Go.

Neuronal death modulators

Because the main pathogenetic characteristic of TSE is neuronal death, several strategies have been designed to prevent or to compensate neuronal depopulation. Most of the cell death that occurs during neurodegenerative processes relates to apoptosis linked either to protein deposition or to neurotoxic mediators secreted through inflammatory processes by glial cells. Therefore, any drug that could impair the molecular cascade associated with neuronal death would be of interest in TSEs. For example, because RORs can be implicated in neuronal death17Go,18Go, ROR scavengers could be used to prevent neurodegeneration54Go. On the other hand, because it is believed that PrP or PrP fragments could participate in neuronal death by inducing apoptosis, several anti-apoptotic drugs have been evaluated in experimental models involving the exposure of neuronal cells to PrP106–12655Go. Some of these (e.g. caspase inhibitors and flupirtine) have shown significant efficiency (flupirtine is a puridine derivative that increases BCl2 expression and antagonises NMDA)56Go.

Clinical data

To date, few open trials have been performed in human TSEs. Those that have been performed were mainly designed as phase I or compassion trials and involved amphotericin B, HPA2329Go,57Go, and more recently quinacrine (JP Brandel, personal communication). None of these drugs has demonstrated a significant effect in CJD (sporadic, familial iatrogenic and some cases of vCJD). Nevertheless, one should note that patient population sizes were low and that most of the patients were in their end-stage at the time of drug administration.


   Immune intervention in TSEs
Top
 Footnotes
 Abstract
 Scientific background to TSE...
 Models for drug screening
 Experimental TSE therapy
 Immune intervention in TSEs
Conclusions
 References
 
TSEs are characterised by a complete lack of detectable specific immune response of infected individuals. This is believed to be related to the particular nature of the infectious agent that is probably composed of the abnormal isoform of the host-encoded PrP. Moreover, no antibody is able to discriminate PrPC and PrPSc. Therefore, immune intervention has often been considered of little use in neurodegenerative diseases. Recently, Schenk and colleagues demonstrated that immunisation of transgenic mice expressing a mutated amyloid protein induces a significant decrease of neurodegeneration59Go; this demonstrated that immune intervention could be possible in neurodegenerative diseases. If so, several strategies can be suggested: (i) eliciting a specific immune response to PrP (e.g. antibodies specific to PrP); and (ii) modulation of innate immunity.

Antibodies directed against some PrP epitopes are able to cure chronically infected cells60Go,61Go. In vivo, transgenic mice harbouring a PrP antibody µ-chain are significantly less susceptible to peripheral infection with the scrapie agent62Go. This proof-of-principle of the efficacy of immune intervention in TSEs has been confirmed recently by: (i) the demonstration of efficacy of vaccination with recombinant PrP prior to or just after infection63Go; and (ii) the increase in survival of animals passively immunised with antibodies directed against PrP (epitopes 91–110 and 149–159)64Go.

Finally, modulation of innate immunity may also provide an efficient tool for post-exposure prophylaxis against prion diseases. Use of CpG oligonucleotides resulted in a significant increase in infected-animal survival, which may be linked to cytokine/chemokine network modulations65Go.


   Conclusions
Top
 Footnotes
 Abstract
 Scientific background to TSE...
 Models for drug screening
 Experimental TSE therapy
 Immune intervention in TSEs
 Conclusions
References
 
At present, there is unfortunately no efficient therapy that can be administered to clinically affected TSE patients. Although the number of publications relating to TSE therapy has increased tremendously during the last 5 years, there are no candidates for a phase II/phase III clinical trial. The development of new strategies that would be applicable to TSEs will require: (i) a complete and exhaustive inventory of human TSE strains; (ii) a precise knowledge of the pathogenesis of all forms of human TSEs, including vCJD, which would permit combined therapy; (iii) a method for infection diagnosis of infected individuals; and (iv) extensive knowledge of the infectious agent.

Different strategies may be applicable depending upon the stage of the infection and the route of exposure of the patient. For example, in principle, it would be of interest to avoid the entry of the agent into the CNS in individuals that are exposed by the peripheral route, although drugs that act on neuro-invasion would not be appropriate in sporadic and familial TSEs. Nevertheless, in clinically affected patients, any efficient drug would have to cross the blood brain barrier and to escape drug efflux mechanisms that are in place in the CNS. Finally, the development of immune intervention strategies on the one hand and the use of neuronal stem cells on the other may provide novel approaches for TSEs and, more generally, neurodegenerative diseases.


   Footnotes
Top
 Footnotes
Abstract
 Scientific background to TSE...
 Models for drug screening
 Experimental TSE therapy
 Immune intervention in TSEs
 Conclusions
 References
 
Correspondence to: Dr Dominique Dormont, Service de Neurovirologie, CEA, CRSSA, EPHE, Univeristé Paris XI, BP 6, 92265 Fontenay-aux-Roses cedex, France


   References
Top
 Footnotes
 Abstract
 Scientific background to TSE...
 Models for drug screening
 Experimental TSE therapy
 Immune intervention in TSEs
 Conclusions
 References
 

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