CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 8, Issue 5, 2009

This month's edition of CNS and Neurological Disorders-Drug Targets is dedicated to the treatment of prion diseases. Although rare, prion diseases are devastating to patients and families. Because of its rarity, the expertise in the field is sparse and misunderstandings are commonplace. Prion diseases are an important field in the study of science in general. They are the only known transmissible diseases that do not utilize nucleic acids and they have sporadic, genetic, and transmissible etiologies. Because of its unique features, the prion disease field has and will continue to contribute to general scientific and medical knowledge. From mathematics (e.g. nucleation) to psychiatry (e.g. stress diathesis), the field of prion diseases has much to offer. Unfortunately, despite our knowledge of the subject, it remains an invariably fatal illness with no current treatment or cure. The articles in this issue illustrate our current knowledge of the disease and its investigational treatments. The veteran researcher, Paul Brown, commences the issue by giving a general overview of the disease and an historical account of its investigational treatments. Dr. Brown shares his wisdom on the evolution of our knowledge regarding the disease and gives useful insight into what can be expected in the future. In a pragmatic fashion, Dr. Brown also highlights the pitfalls of developing investigational treatments and proposes important points for prion disease researchers to ponder when developing treatment strategies. Surachai Supattapone and colleagues present a review on the use of complex polyamines for the treatment of prion diseases. Although the majority of investigational treatment approaches have targeted the conversion of the native prion protein (PrPc) to the pathological prion protein (PrPres), the authors suggest a different therapeutic model. Complex polyamines serve two rules in combating prion disease: 1) disaggregation of amyloid proteins and 2) clearance of prions from cells. This approach posits the possibility of treating active disease as opposed to slowing its propagation. An article by Constance Riemer and colleagues examines prion diseases from an immunological perspective. Addressing the reactive astrogliosis that is characteristic of prion diseases, Reimer and colleagues focus on the possible inflammatory reactions caused by PrPres accumulation. They propose anti-inflammatory treatments that target pro-inflammatory cytokines in the hope of delaying disease progression by mitigating the toxic effects of PrPres accumulation.

Efforts to treat transmissible spongiform encephalopathy (TSE) date back to the middle of the 20th century. Early studies were colored by the belief that TSE was caused by a ‘slow’ or ‘unconventional’ virus, and a variety of antiinfective agents, together with scores of drugs drawn at random from other categories, predictably failed to provide any benefit, apart from polyanionic compounds and polyene antibiotics that prolonged the incubation period of disease in experimental animals. With the discovery in the 1980's that TSE apparently results from the malformation of a normal host protein, attempts at treatment could at last be rationally focused, and can be broadly categorized as genetic, immunologic, and pharmacologic. Genetic ‘neutralization’ of the pathogen has shown excellent results in experimental animals but is unlikely to be useful until the same kind of engineering can be effectively applied to humans. Immunologic methods to accomplish the same result have also shown some success in animals, but forays into the pharmacologic realm have been generally disappointing. Most reported ‘successes’ have been limited to prolonged incubation periods, and even then only when the treatment was begun at or near the time of infection, which is not known in sporadic or familial human disease. However, a few methods using the more rigorous model of treatment nearer the onset of symptomatic disease have begun to yield promising results that, if coupled with a practical screening test for pre-clinical infection, would be the optimal strategy for prevention or cure.

Among the candidate anti-prion chemotherapeutic agents identified to date, complex polyamines constitute the only class of compounds that possess the ability to remove pre-existing PrPSc molecules from infected cells. The potency of branched polyamines such as cationic dendrimers increases with the density of positive charges on their surface. Cationic dendrimers appear to accumulate together with PrPSc molecules in lysosomes, where the acidic environment facilitates dendrimer-mediated PrPSc disaggregation. Dendrimers can disaggregate a range of different amyloid proteins by interacting with specific epitopes on each protein. Studies with model peptides suggest that dendrimers may cause fiber breakage and capping of elongating fibers. Potential limitations to the development of dendrimers as therapeutic compounds for neurodegenerative disorders of protein misfolding such as prion diseases include poor bioavailability, limited spectrum of activity, and detrimental neurological side effects. A related group of compounds, lipopolyamines, are smaller molecules containing a lipophilic tail that may assist membrane targeting. Developing strategies to enable the safe delivery of potent complex polyamines to the central nervous system represents a critical avenue for future research.

Prion infections of the central nervous system (CNS) are characterized by a reactive gliosis and the subsequent degeneration of neuronal tissue. The activation of glial cells, which precedes neuronal death, is likely to be initially caused by the deposition of misfolded, in part proteinase K-resistant, isoforms (termed PrPTSE) of the normal cellular prion protein (PrPc) in the brain. Proinflammatory cytokines and chemokines released by PrPTSE-activated glial cells and stressed neurons may contribute directly or indirectly to the disease development by enhancement and generalization of the gliosis and via cytotoxicity for neurons. Recent studies have illustrated that interfering with inflammatory responses may represent a therapeutic approach to slow down the course of disease development. Hence, a better understanding of driving factors in neuroinflammation may well contribute to the development of improved strategies for treatment of prion diseases.

Effective treatment of neurodegenerative disease is one of the major challenges facing biomedical research. These disorders, which include Alzheimer's, Huntington's and Parkinson's diseases - as well as the rarer prion diseases - constitute an ever-increasing burden in the developed world, socially, medically and economically. The key barrier to effective therapy is that they present clinically when neuronal loss is advanced, and irreversible. Current treatments are almost all directed at modifying symptoms; few address underlying pathogenic mechanisms and are inevitably delivered too late to rescue dying neurons. In the field of prion diseases, however, insights into the molecular basis and the temporal evolution of prion neurotoxicity are increasing. Recent work in mice leads to new hope for the treatment of these disorders, and potentially for rescuing neurodegeneration more broadly. Using lentivirally mediated RNA interference (RNAi) against native prion protein (PrP), White et al report the first intervention resulting in neuronal rescue, prevention of symptoms and increased survival in mice with established prion disease [1]. Central to the effectiveness of this strategy are both the target and the timing of the intervention: the treatment prevents the formation of the neurotoxic prion agent at a point when diseased neurons can still be saved from death. This review introduces the basic concepts of prion pathogenesis, emerging insights into mechanisms of prion neurotoxcity and the rationale for targeting endogenous prion protein (PrP) in prion therapeutics. It describes the discovery of a window of reversibility of early neuronal damage in prion disease and how together these advances led to the subsequent development of the strategy using RNAi based therapy for these disorders. It discusses the use and relevance of this approach more broadly in neurodegeneration.

Prion diseases are rare, rapidly progressive, fatal neurodegenerative illnesses caused by an abnormal isoform of the native prion protein. Creutzfeldt-Jakob disease (CJD) is the most prevalent human prion disease with three possible etiologies: sporadic, genetic, and acquired. Although acquired forms of prion disease have received the most attention, most cases are sporadic or genetic and are thus unpreventable. There is some literature on neurotransmitter system dysregulation in animal and human models of prion diseases. Several studies indicate that there is a disproportional amount of serotonin dysregulation in prion diseases and that prion-mediated cytotoxicity may be blocked by N-methyl Daspartate (NMDA) receptor antagonists. Prion disease therapeutic investigations have mainly consisted of basic science research, which has elucidated the importance of molecular structure in preventing prion protein conversion. Typical neuroleptics and tricyclic antidepressants have been the primary psychotropic medications studied in humans due to their heterocyclic structures. Recent studies have correlated lipid disruption to these structurally similar compounds with antiprion activity. Preliminary studies suggest that lithium mediated inhibition of glycogen synthetase kinase 3 and lithium-induced autophagy may be avenues for further research. Many studies require replication in other experimental settings. Thus far, treatment strategies have focused on aborting prion protein conversion and as such have limited therapeutic usefulness given the rapidity of disease progression and difficulty in establishing ante-mortem diagnoses of prion diseases. There is a paucity of research examining the prevention of prion diseases in at risk populations (i.e. genetic and acquired prion diseases).

Protein Misfolding Disorders (PMDs) are a group of diseases characterized by the accumulation of abnormally folded proteins. Despite the wide range of proteins and tissues involved, PMDs share similar molecular and pathogenic mechanisms. Several epidemiological, clinical and experimental reports have described the co-existence of PMDs, suggesting a possible cross-talk between them. A better knowledge of the molecular basis of PMDs could have important implications for understanding the mechanisms by which these diseases appear and progress and ultimately to develop novel strategies for treatment. Due to their similar molecular mechanisms, common therapeutic strategies could be applied for the diseases in this group.

Creutzfeldt-Jakob disease (CJD) is a rare, degenerative and fatal brain disease that appears to be caused by an abnormal form of a protein called a prion. Due to the lack of an effective treatment for CJD, support for patients and family members is crucial. Appropriate education of the healthcare community on this rare disease and provision of palliative care are critically needed. The CJD Foundation and CJD Insight were formed to provide services to patients and families affected by prion diseases.

Diabetes insipidus and neurodegenerative disease are the two major central nervous system (CNS) complications of Langerhans cell histiocytosis (LCH). Once it has developed, diabetes insipidus is permanent, while the outcome of neurodegenerative disease is dismal. The development of these CNS-LCH complications is closely correlated with “CNS-risk” organ involvement, namely, the presence at diagnosis of LCH lesions in cranio-facial areas. Based on recent data showing the beneficial effects of intravenous immunoglobulin (IVIG) treatment on inflammatory diseases of the CNS, we are currently testing whether monthly IVIG treatment (0.4 g/kg/dose) can alleviate the progression of neurodegenerative disease in LCH patients. We also hypothesize that the incidence of CNS complications could be reduced by the prophylactic administration of high dose IVIG therapy (2 g/kg/dose), combined with conventional induction chemotherapy, that is provided before CNS lesions are detected in “CNS-risk”-LCH patients.

Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia characterized by an abnormal fusion protein, PML/RARA. All-trans retinoic acid (ATRA) and arsenic trioxide, which are the major molecularly targeted therapies in APL, affect or degrade the PML/RARA fusion protein and cause differentiation and apoptosis of APL cells. These therapies have improved the prognosis of APL patients and are now the main therapeutic options in APL. In addition, gemtuzumab ozogamicin is another targeted therapy in APL. On the other hand, the prognosis of patients with central nervous system (CNS) relapses of APL remains poor. Therefore, CNS relapses have become major concerns, and effective therapeutic approaches for CNS relapses are needed. In fact, possible active roles of molecularly targeted therapies in CNS relapses of APL have been suggested, and several new approaches with molecularly targeted therapies for CNS relapses have been examined in APL. In this review, we discuss three main topics; the relationship between the incidence of CNS relapses and the introduction of molecularly targeted therapies for APL, new approaches with targeted therapies for CNS relapses of APL, and other complications of targeted therapies in CNS such as pseudotumor cerebri induced by ATRA and subarachnoid hemorrhage. This comprehensive understanding would be helpful for better management of patients with APL.

Aptamers are short non-naturally occurring single stranded DNA or RNA able to bind tightly, due to their specific three-dimensional shapes, to a multitude of targets ranging from small chemical compounds to cells and tissues. Since their first discovery, aptamers became a valuable research tool and show great application to fundamental research, drug selection and clinical diagnosis and therapy. Thanks to their unique characteristics (low size, good affinity for the target, no immunogeneicity, chemical structures that can be easily modified to improve their in vivo applications), aptamers may represent a valid alternative to antibodies particularly for the treatment of neurological disorders that urgently need modalities for drug delivery through the blood brain barrier. Aptamers have excellent potential as reagents for the targeted delivery of active drug substances, either through direct conjugation to the aptamer, or through their encapsulation in aptamer-coated vesicles. We will review here the recent and innovative methods that have been developed and the possible applications of aptamers as inhibitors or tracers in neurological disorders and brain cancer.