Adjunctive Therapies For Neurodegenerative Disorders

Many diverse mechanisms, factors, and pathways are involved in neurodegenerative disorders, thus several different therapeutic methods have been developed to target a specific factor or a whole intricate pathway with the intent of ameliorating, preventing, or reversing neuronal cell damage. Inflammation and oxidative stress form a commonality between many neurode-generative diseases; therefore most therapeutic modalities currently under investigation target MP activation to decrease the magnitude of the inflammatory responses (Fig. 19.4). The targets of these therapies include, but are not restricted to, enhancement of neurotrophic factors (brain-derived neurotrophic factor [BDNF], glia cell-line derived neurotrophic factor [GDNF], and nerve growth factor [NGF]), up-regulation of anti-inflammatory cytokines (IL-4, IL-10, and TGF-P1), inhibition of enzymatic activities that encourage neurotoxicity (GSK-3P, g-secretase), Ca2+ and glutamate excitotoxicity blockers that inhibit NMDA receptor function, suppression of neuronal cytotoxicity (memantine, lithium, sodium valproate), and attenuation of inflammation by anti-inflammatory drugs (NSAID, minocycline) (Fig. 19.4A). Novel approaches are currently being developed to attenuate aggregation of misfolded proteins with antibodies and the use of T-cell-mediated immune responses to attenuate neuroinflammation. Anti-inflammatory and/ or anti-oxidative therapies could be used in conjunction to form combinational therapies targeting multiple sites of oxidative stress that contribute to inflammation responses and progressive disease.

Presently there is a push for interdisciplinary research designed to find specific biomarkers for earlier diagnosis of disease. This research has been made possible by the development of novel proteomic, ge-nomic, and metabolomic assays and cellular systems designed to replicate human disease. The development of sensitive clinical tests and advancement of imaging capabilities with SPECT and MRI will also lead to earlier diagnosis. Currently, treatment for neurodegenerative diseases begins long after neurodegeneration has started, after its detrimental effects become symptomatic. The failure in late- or end-stage clinical trials of promising therapeutic modalities emphasizes the need for presymptomatic treatment.

Neurodegeneration in HAD, PD, AD, ALS, and other neurodegenerative diseases seems to be

figure 19.4. Adjunctive treatments of HIV-1 and other neurodegenerative disorders. A number of adjunctive therapies are being developed for treatment of HIV-1-associated cognitive impairments. These are directed at pathogenic mechanisms for disease, including those that affect viral replication, modulate neuroinflammation, interdict cell signaling events that lead to neuronal demise, or affect cell migration into the brain or the viral replication cycle (A). Novel approaches are now under development to harness the host's own immune system to combat disease. These methodologies currently involve direct immunization strategies and novel nanoparticle delivery systems (B). GA, glatiramer acetate; MDM, monocyte derived macrophages; MP, mononuclear phagocyte; PAF, platelet-activating factor; PPARg, peroxisome proliferator-activated receptor gamma.

multifactorial, in that a complex set of toxic reactions including inflammation, glutamatergic neurotoxicity, increases in iron and nitric oxide, depletion of endogenous antioxidants, reduced expression of trophic factors, dysfunction of the ubiquitin-proteasome, and expression of pro-apoptotic proteins leads to the demise ofneurons. As a result, the gradual accumulation of neuronal death and the increase in disease severity across time is a unifying theme across the diverse classifications of neurodegenerative disease. Thus, while the triggers of various neurodegenerative diseases are diverse, inflammation may be a basic mechanism driving the progressive nature of multiple neurode-generative diseases. With complete comprehension of the cellular and molecular mechanisms and of the specificities of inflammation in these neurological disorders, therapeutic strategies to prevent or slow the progression of these destructive diseases can be delineated. The combinatorial use of therapeutic modalities that target inflammatory processes might aid in providing supportive treatment of HAD, AD, PD, and ALS.

The dementia produced by CNS infection with HIV elicits a cascade of events involving both resident and invading cell types and ultimately the devastating loss of neuronal function and increase in cognitive deterioration. Treatment failures, viral mutation drug-associated disease, and evolving neurological syndromes support the importance of neurological impairments as a significant part of the overall disease complex. In the past decade we have seen a milder phenotype and decreased incidence of HAD, largely due to the widespread use of combination chemotherapy to reduce viral burden. However, the prevalence of neurological disease in people living with HIV-1 has actually increased, raising significant concerns that new therapeutic strategies, directed at restoring neuronal and glial homeostasis and signaling in the CNS, as opposed to directly interfering with the life cycle of HIV-1, must be developed. Researchers developing new agents and strategies for the management of HIV-1 disease are focusing on regimens that include novel targets and are simpler and better tolerated, with decreased potential for development of viral resistance. Because the disease process occurs in a stepwise fashion, it provides the opportunity for development of therapeutics directed at discrete pathogenic mechanisms. Although antiretroviral agents are currently the only therapy in general use for treatment of AIDS dementia, a clearer understanding of the neuropathogenesis of HIVE and HAD has al lowed the selection of rational adjunctive therapies for HAD that are now in development. Phase 1 clinical trials for adjunctive (i.e., chemotherapeutic agents that do not have a primary antiretroviral mechanism of action) therapy in patients with HAD have been conducted.

There are several reasons for the demand for such therapies. First, antiretroviral therapy, while successful in decreasing viral burden and delaying the onset of HAD, does not prevent it. Second, combination antiretroviral therapies are not always well tolerated. Third, only a very limited fraction of the global population of HIV-infected persons has access to antiretrovirals. Fourth, HIV-1 is able to adapt to most of the antiretroviral agents. Also, most antiretroviral agents do not freely cross the BBB. Finally, overlapping pathogenic mechanisms are operative for other neuro-degenerative disorders containing an inflammatory component, making it likely that agents will have crossover potential for treatment of a wide range of neurodestructive processes.

Antiretrovirals

Prior to the advent of potent antiretroviral therapy, HIV infection was characterized as an acute, systemic infection that rapidly led to immune suppression and cognitive decline. With the development of antiret-roviral therapies, extended life expectancies and a better quality of life never before anticipated for patients with AIDS have been achieved. The decision to start antiretroviral therapy is largely based on CD4+ T-cell count thresholds, although higher viral load has been shown to increase risk of disease progression. Current guidelines recommend treatment for all patients with symptomatic HIV disease or AIDS and for asymptomatic patients with CD4+ T-cell counts <200 cells/mm3 (Swindells et al., 1999). Since HIV-1-infected brain MP initiate the inflammatory neuro-immune cascade in the brain, leading to neuronal dysfunction, it is vital that any therapeutic strategy includes the use ofantiretroviral agents to decrease the CNS viral load. Indeed, sufficient doses of 3'-azido-3'-deoxythymidine (AZT) can produce clinical improvement in the mental function of HIV-1-infected individuals (Schmitt et al., 1988; Llorente et al., 2001). Many antiretroviral agents are currently in use; these can be classified into specific categories based on function, including nucleoside reverse transcriptase inhibitors (e.g., zidovudine [AZT], didanosine

[DDI]), nonnucleoside reverse transcriptase inhibitors (e.g., nevirapine, delavirdine), protease inhibitors (e.g., indinavir, ritonavir), and combination antiret-roviral therapy (Chang et al., 1999b; Ammassari et al., 2000; Gray and Keohane, 2003; Dou et al., 2004). While antiretroviral agents are beneficial in attenuating viral load, complications associated with infection are still prevalent, as the virus is never wholly eliminated. Antiretroviral medicines fail to completely eradicate the virus, in part because of a latent form of the virus that persists in resting memory CD4+ T cells (Finzi etal., 1997; Ho etal., 1998; Silician etal., 2003) and select viral mutations that result in viral resistance to antiretroviral drugs (Johnson et al., 2005). Viral reservoirs represent a potentially lifelong persistence of replication-competent forms ofHIV-1, recovered from resting CD4 T cells (Finzi et al., 1997) and peripheral blood monocytes (Crowe and Sonza, 2000), that cannot be suppressed by current antiretroviral treatments. Primary and acquired antiretroviral resistance rates reflect the relative usage of different antiretroviral drugs in the population, as well as the inherent genetic barrier to the development of resistance associated with individual drugs. Data on antiretroviral resistance rates, gleaned from the growing HIV-1-infected population treated with a continuously increasing number of antiretroviral drugs and drug combinations, provide insight to the relative ease by which HIV-1 escapes the selective pressure of chronic drug exposure. Strains of HIV-1 that are resistant to reverse transcriptase and protease inhibitors arise in the majority of treated patients who have either poor adherence to the treatment regime or low plasma drug levels for other reasons (Kedzierska et al., 2003). Most important, virus resistance to drugs heralds increased viral loads, immune suppression, and the onset of neurological impairments associated with advanced viral infection. The development of novel adjunctive immunotherapies to use in combination with antiretroviral drugs provide new therapeutic strategies to combat infection that will be better tolerated and have a decreased potential for the emergence of viral resistance. New research will continue to provide more options for such patients, with new treatments and eventually vaccines on the horizon.

Glutamate Receptor Antagonists

The use of NMDA-receptor antagonists is a good example of this approach. Neuronal dysfunction and death that occur in HIVE and are associated with HAD might ultimately be mediated by pathologic activation of excitatory subtypes of glutamate receptors, in particular the NMDA receptor (Lipton, 1992, 1994; Lipton et al., 1994). Numerous examples in the literature demonstrate the involvement of NMDA and non-NMDA receptor activation in vulnerable neurons after exposure to HIV-1-associated neurotoxins. One problem in designing a practical therapeutic approach to ameliorating excitotoxic neuronal damage is that most of the available small-molecule agents that block ionotropic receptors function as uncompetitive or noncompetitive channel antagonists. Thus, administration of such an agent at concentrations that might be neuroprotective in the CNS might also significantly interfere with fast excitatory neurotransmission. Thus far, the most promising NMDA antagonist currently in clinical trials for HIV-1-related neurological disease is memantine. This NMDA-receptor antagonist is an open channel blocker and has been shown to attenuate the neuronal damage induced by HIV-infected macrophages and gp120 (Jain, 2000).

GSK-3 Inhibitors

The GSK-3 inhibitor sodium valproate (VPA) has been proposed to possess neuroprotective properties as a result of its effects on GSK-3b activity (Tong et al., 2000) and because of its cytoprotective effect on neurons exposed to candidate HIV neurotoxins. VPA has already been used in HIV-1-infected individuals to manage psychiatric disorders and was generally well tolerated. VPA is preferable to the other presently available inhibitor of GSK-3b, lithium, in light of its greater tolerability in HIV-positive individuals and lack of toxic side effects.

Dopaminergic Agents

In HIV-1-infected individuals, neurological disease has been linked to changes in DA metabolism, and DA levels within the CSF are reduced. Furthermore, experiments conducted with cell culture have shown that HIV-1 gp120 is toxic for dopaminergic neurons (Bennett et al., 1995). On the basis of these findings, it has been proposed that alterations in DA metabolism may contribute to motor deficits in persons with HAD and possibly to other aspects ofthis disease. Therefore, DA agonists such as pramipexole, shown to be neuro-protective in a mouse model in the context of MPTP-

induced injury, have been proposed for treatment of HIV infection (Hall etal., 1996; Cassarino etal., 1998; Kitamura et al., 1998a, 1998b). Pramipexole had been shown to up-regulate the expression of anti-apoptotic proteins such as Bcl-2, and to protect cultured neurons from pro-apoptotic insults (Takata et al., 2000). Furthermore, Bcl-2 can mediate neuroprotection against candidate HIV-1 neurotoxins, including HIV-1 Tat and TNF-a.

PAF Receptor Antagonist

PAF is a phospholipid mediator that may play a key role in NMDA receptor activation in HAD (Bito et al., 1982). Intriguingly, in vivo experiments using the SCID mouse model of HIVE demonstrate that PAF receptor antagonists are neuroprotective (Persidsky et al., 2001). A phase I trial of tolerability of the PAF receptor antagonist lexipafant in a cohort of patients with varying stages of HAD demonstrated trends in improvement of neuropsychological parameters, including verbal memory (Schifitto et al., 1999, 2001). These trends were promising enough to extend the cohort size and dosing schedule into an ongoing trial of efficacy.

PPARg Agonists

Peroxisome proliferator-activated receptor gamma (PPARg) is a nuclear receptor involved in monocyte-derived macrophage differentiation. Agonists for this receptor, such as cyPG, PgJ, and troglitazone, have been shown to inhibit HIV-1 replication in vitro in T-cell lines (Hughes-Fulford et al., 1992) in chronically infected macrophages (Rozera et al., 1996) and, more recently, in acutely infected monocytes (Hayes et al., 2002; Skolnik et al., 2002).

Immunotherapy

There is renewed interest in the use of immunother-apy as an adjunct to antiretrovirals in the treatment of HIV disease. A number of cytokines have been proposed as modulators of HIV-specific effector functions, the most studied being IL-2. Subcutaneous IL-2 administered to patients with HIV-1 infection has been shown to facilitate CD4+ T-cell expansion, facilitated by the selective induction of the alpha chain (CD25) of the high-affinity IL-2 receptor complex on CD4+ T cells (Kovacs et al., 1996a, 1996b; Pett and Emery, 2001). Clinical trials have demonstrated that intermittent administration of IL-2 to HIV-1-infected patients in combination with antiretrovirals results in substantial and significantly higher CD4+ T-cell increases than those achieved with antiretroviral therapy alone (Kovacs et al., 1996a, 1996b; Davey et al., 1997; Pett and Emery, 2001). Other cytokines that contribute to enhancing macrophage function, including GM-CSF and IFN-g, have also been proposed as immunomodulators for use in immunotherapy. The main caveat however, is that without effective anti-retroviral therapy, these cytokines can promote HIV-1 replication (Kaplan et al., 1991; Krown et al., 1992a, 1992b). Indeed, GM-CSF is known to stimulate the proliferation and differentiation of cells of the macrophage lineage; it has also been shown to increase the phagocytic activity of these cells (Krown et al., 1992b; Eischen et al., 2001). Even so, GM-CSF has been shown to augment the effects of antiretroviral therapy. Data show that patients receiving GM-CSF in combination with antiretroviral therapy experienced a decrease in viral load and an increase in CD4+ T-cell count (Brites et al., 2000).

Glatiramer Acetate Immunization

Glatiramer acetate (GA, Copaxone, copolymer-1) is an FDA-approved immunomodulatory drug for the treatment of multiple sclerosis (MS). GA immunization induces Th2 regulatory T lymphocytes secreting anti-inflammatory cytokines in mice and humans. These T cells migrate to the brain and provide bystander suppression against neuroinflammation. GA was shown to be an effective immunomodulatory treatment for neuroprotection in animal models of experimental autoimmune encephalomyelitis, optic nerve crush, PD, and AD (Kipnis et al., 2000; Benner et al., 2004; Weber et al., 2004; Frenkel et al., 2005; Wolinsky, 2006). In addition, clinical trials are ongoing in the use of GA in the treatment of ALS (Gordon et al., 2006). A newly completed study in our own lab tested the effects of GA immunization on neuropath-ological outcomes in rodent models of HIVE. GA administration resulted in significant neuroprotection accompanied by increased levels of IL-10 and BDNF (Gorantla et al., submitted). Immunization with GA is probable, as it is already approved for treatment of MS, it is able to boost immune responses of both the Th1 and Th2 phenotype, and it has been used without side effects in a phase 1 study of ALS (Weber et al., 2004; Gordon et al., 2006).

Nanoparticle Drug Delivery

The limitations of antiretroviral therapy in the long-term treatment of HIV-1, which include cost, treatment failures, dosing complexities, and drug toxicity, are beginning to be realized (Chen et al., 2002; Chulamokha et al., 2005). As a result, a global effort has been undertaken to develop novel therapeutic strategies to address these limitations. Recently, we described a nanoparticle (NP) system that was developed in our lab, in conjunction with Baxter Pharmaceuticals. The nanoformulation is designed to improve therapeutic efficacy of antiretroviral drugs through a delivery system capable of distributing drug to areas of active viral replication, as well as to extend dosing intervals (Dou et al., 2006). Because of the small and highly stable NP formulation, we were able to package the particles within macrophages to be delivered through systemic trafficking within the host. In a single dose, the NP containing the drug trafficked to the site of inflammation in the CNS (visualized by MRSI), had sustained drug release over a period of 2 weeks, and presented with antiretroviral activity. Toxicity was not evident during the administration period (Fig. 19.4B). The treatment of HIV-1, which requires lifelong therapy, with a similar nanoformu-lation could affect therapeutic outcome and drug usage in the developing world.

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