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Therapeutics in Alzheimer’s Disease

By Joel Ross | June 7, 2010

I have attached a copy of a section covering current treatments for AD reprinted from the following article:
My take on this approach is as follows: Similar to Baxter’s approach using their “Gamma Guard” it will take time to determine if this approach is truly meaningful to patients.

AMYLOID-TARGETED THERAPEUTICS IN ALZHEIMER’S DISEASE: USE OF HUMAN ALBUMIN IN PLASMA EXCHANGE AS A NOVEL APPROACH FOR Aβ MOBILIZATION
by Mercè Boada, Pilar Ortiz, Fernando Anaya, Isabel Hernández, Joan Muñoz, Laura Núñez, Javier Olazarán, Isabel Roca, Gemma Cuberas, Lluís Tárraga, Mar Buendia, Ramón P. Pla, Isidre Ferrer and Antonio Páez
Drug News & Perspectives
Vol. 22, No. 6, 2009, pp. 325-339
Copyright © 2009 Prous Science, S.A.U. or its licensors. All rights reserved.
CCC: 0214-0934/2009
DOI: 10.1358/dnp.2009.22.6.1395256

THERAPEUTICS

Current management: preventing decline of cognitive mechanisms

Despite years of intensive research, a safe and effective treatment has not yet been encountered. The currently approved therapies are only available for the symptomatic treatment of AD, show no long-term efficacy, and do not prevent disease progression. Current therapeutic agents include cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists.

There is evidence that biological dysfunction or imbalance in neurotransmission, particularly cholinergic and glutamatergic, is involved in the etiology of AD. The neurotransmitter acetylcholine is essential for processing memory and learning. Deficits in both concentration and function of acetylcholine have been found in patients with AD, caused by either a loss of cholinergic neurons or decreased acetylcholinesterase activity.37 Cholinesterase inhibitors have a moderate but worthwhile effect in stabilizing symptoms. The current drugs (donezepil, rivastigmine and galantamine) are adequate for mild and moderate AD.38-41 On the other hand, overactivation of NMDA receptors, which are pivotal in learning and memory, by the neurotransmitter glutamate has been linked to neuronal damage that may result in cognitive decline in patients with AD.37 Memantine is a partial NMDA receptor antagonist that appears to be effective in slowing down cognition decline in moderate to severe AD patients.42

However, the search for effective treatment strategies for AD continues and special attention is being paid to potential targets for drug and therapeutics development, such as the enzymes and molecules involved in the mechanisms that can lead to the development of the disease. A number of products targeting not only Aβ formation and aggregation but also tau pathology, oxidative stress, inflammation, excitotoxicity and neurodegeneration are currently under active investigation.43-45

New perspectives: targeting neuritic plaque

Among the many novel therapeutic approaches under investigation for AD, strategies oriented towards reducing the production of cytotoxic Aβ in order to prevent the accumulation of amyloid deposits or to reduce the existing neuritic plaque seem particularly appealing.46 Pharmacologic targets as detailed in the following sections and points of action of putative therapeutic agents can be seen in Figure 1.

Reduction of APP

Modulation of APP production is the top upstream targeting of Aβ. Intracellular trafficking of APP may be regulated by multiple factors such as signal transduction enzymes or hormone stimulation. Interfering with these factors may affect intracellular levels of APP and thus the proteolytic processing of APP, thereby reducing the overall levels of Aβ. Compounds such as phenserine, an acetylcholinesterase inhibitor, and deferoxamine, a Fe3+ chelator, have been also described as possessing the capacity to lower the rate of APP messenger RNA synthesis, resulting in a substantial reduction of Aβ levels.47,48 In a phase III clinical study, however, phenserine failed to demonstrate efficacy compared to placebo in cognition tests.

Activation of a-secretase

Favoring APP processing through the neuroprotective, nonamyloidogenic pathway seems to be a logical alternative strategy to reduce the burden of cytotoxic Aβ. This process should involve the pharmacological activation or upregulation of a-secretase. Multiple enzymes have been identified as possessing a-secretase-like activity. Four members of the ADAM (a disintegrin and metalloproteinase) family, ADAM 9, ADAM 10, ADAM 17 (TACE) and more recently ADAM 19, have been proposed as a-secretases.49,50 In particular, ADAM 10 has been postulated to exert a predominant role in vivo as the physiologically relevant constitutive a-secretase.51 Competition between a-secretase and b-secretase for the substrate APP has been demonstrated in vivo, and evidence suggested that overexpression of ADAM 10 inhibited the production of Aβ, prevented plaque formation and alleviated the associated neurological effects.52 Several mechanisms for a-secretase upregulation have been described, including ADAM10 gene expression enhancement and stimulation of molecular signaling.51 Moreover, low cholesterol levels have been associated with higher levels of a-secretase ADAM 10 activity.53 Statins (e.g., batimastat, marimastat, simvastatin, atorvastatin) are well-known cholesterol-lowering drugs that have been suggested to regulate a-secretase resulting in anti-AD efficacy.54,55

Inhibition of b-secretase

As one of the major players involved in the neurotoxic Aβ-generating amyloidogenic pathway, b-secretase may be a key therapeutic target against AD. b-Secretase is an integral membrane aspartyl protease primarily expressed in the brain and often termed BACE1 for b-site APP-cleaving enzyme 1.56 While recent reports indicate that BACE1 expression is tightly regulated, proposed physiological roles include participation in a wide range of processes such as axonal growth, brain development and myelination, although many of these functions within the central nervous system are not completely understood.57 Overexpression of BACE1 is associated with neurodegeneration and BACE1 is upregulated in at least some AD brains.58 Development of effective BACE1 inhibitors has proven challenging, mainly due to difficulties found in successful BBB crossing and delivery to the brain.59 Current BACE1 inhibition agents under investigation include OM-99-1, OM-99-2, ATG-Z1 and CTS-21166.55,60

Inhibition/modulation of g-secretase

g-Secretase is a high-molecular-weight complex composed of four major membrane proteins: presenilin 1 (PS1), nicastrin (NTC), presenilin enhancer 2 (PEN-2) and anterior pharynx defective 1 (Aph-1). g-Secretase is ubiquitously expressed and can cleave a number of different membrane proteins besides C99. Notch 1 receptor is a particularly relevant substrate of g-secretase.61 Notch signaling regulates the capacity of neurons to extend and elaborate neurites but it is also involved in embryogenesis as well as cell differentiation and maturation events in adulthood. For these reasons, g-secretase inhibitors (e.g., begacestat, MK-0752 and flurizan, although the latter failed in a phase III clinical study) can interfere with vital physiological processes causing toxicity.62 Research for alternatives to g-secretase inhibitors is focused on the development of selective C99 proteolysis blockers (e.g., imatinib, LDDN-9918) and g-secretase modulators capable of reducing the formation of pathogenic Aβ40 and Aβ42 (e.g., ibuprofen, indomethacin), allowing g-secretase to generate shorter, less fibrillogenic Aβ peptides.63

Interfering with Aβ aggregation

AD neurotoxicity is thought to result from the aggregation of Aβ into growing amyloid fibrils that form neuritic plaques.64 As a consequence, downstream strategies targeting Aβ with the intention to inhibit this aggregation or to disrupt the already formed amyloid plaque in brain tissue are currently under investigation (e.g., immunotherapy, small-molecule pharmacotherapy, metal chelation).65

Immunotherapy with Aβ-specific antibodies, which includes active (vaccination) or passive immunization, is thought to act through several mechanisms of action. Antibodies against Aβ can prevent the formation of plaques in some animal models and in humans,66 although these treatments are associated with deleterious immune reactions.67,68 Antibodies can bind Aβ in fibrils and plaque, thus favoring disaggregation, producing soluble forms of Aβ that can be eliminated from the body.69 However, plaque-directed antibodies are required to cross the BBB. It is thought that antibodies can enter the brain by passive diffusion at sites deficient in BBB.70 Moreover, Aβ-antibody complexes may be cleared by FcRn receptor-mediated transcytosis across the BBB.71

Small-molecule inhibitors of Aβ aggregation under active development include Colostrinin, AZC-103, SEN-606, and even natural products derived from Gingko biloba, curcumin and nicotine. The Aβ aggregation inhibitor tramiprosate (Alzhemed®) failed to show significant differences versus placebo in AD patients. Amyloid plaque degradation enhancers include small molecules such as aleplasinin (PAZ-417) as well as short synthetic peptides that could be active in disrupting the stability of the b sheet.

There is evidence that certain metal ions (Cu2+, Fe3+ and Zn2+) play a role in the precipitation of cytotoxic Aβ. In this sense, the possible capacity of metal chelators such as iodochlorohydroxyquin and PBT-2 (the product that replaced the withdrawn clioquinol) to reverse amyloid-b plaque deposition is under investigation.72,73

Aβ clearance

In addition to antibody- or drug-mediated Aβ degradation in brain, extracellular monomeric Aβ can be cleared from the brain to the periphery, where it can then be degraded or removed. The concentration of Aβ in brain interstitial fluid is tightly regulated through transport across the BBB (Fig. 1). LRP1 is the major cell surface transporter protein involved in Aβ clearance through transcytosis from the brain to the blood,74 while the RAGE mediates soluble Aβ influx into the brain across the BBB.75 RAGE is a potential target for therapies aimed at lowering the Aβ load in brain. Inhibitors of RAGE-Aβ binding currently in the pipeline for mild and moderate AD include PF-04494700 (phase II development).

There is growing evidence that Aβ levels in AD are increased in plasma and decreased in CSF.76 This observation has led to the design of novel therapeutic strategies proposed to clear Aβ from the brain through the induction of an unbalance of Aβ transport dynamics across the BBB. Thus, the sequestration of Aβ in plasma may both increase the transport of free Aβ from CSF to plasma and reduce Aβ transport into the brain in order to restore the intrinsic equilibrium between brain and blood Aβ levels.77 Immunotherapy with antibodies binding to and clearing plasma Aβ has the advantage of not having to undergo BBB crossing and is proven capable of reducing brain amyloid burden in mouse models.78

A novel approach: plasma exchange with albumin replacement

Plasma exchange is a process used to eliminate patient’s plasma and replacing it with another solution in order to maintain normal volemia and osmotic balance. To achieve this effect, albumin or other colloids have been used, as well as fresh frozen plasma and crystalloids. The purpose of this procedure is to eliminate toxic substances from patient plasma, such as autoantibodies, alloantibodies, immune complexes, proteins or toxins. Plasma exchange is widely used in the treatment of different pathologies. Specifically, this procedure has been applied to the following disorders: Guillain-Barré syndrome,79 multiple sclerosis,80 inflammatory demyelinating polyradiculoneuropathy,81 acute inflammatory demyelinating disease of the CNS82 and other peripheral neurological alterations.83

Here, plasma exchange is presented as a novel approach for the treatment of AD with a focus on plasma Aβ clearance, taking into account the fact that 90% of circulating Aβ may be bound to albumin.84 Hence, the potential mobilization of plasma Aβ bound to therapeutic albumin through plasma exchange could in turn translate into a mobilization of brain Aβ and, as a consequence, lead to an improvement of the patient’s cognitive functions.

With this in mind and taking into account that preliminary studies have demonstrated that Human Albumin Grifols® is able to bind Aβ peptide,85 a clinical investigation program using Human Albumin Grifols through a plasma exchange regimen in patients with mild to moderate AD was carried out.

CLINICAL INVESTIGATION PROGRAM OF Aβ MOBILIZATION THROUGH ALBUMIN BINDING AND PLASMA EXCHANGE IN MILD to MODERATE AD

Pilot study (proof-of-concept)

The first clinical study carried out was a pilot study aimed to assess whether Human Albumin Grifols was able to mobilize plasma Aβ peptide when used in a therapeutic plasma exchange program at a rate of two plasma exchanges per week during 3 weeks, that is, 6 plasma exchanges in total. Furthermore, a possible change in the cognitive status was also assessed through neuropsychological evaluations.

During each plasma exchange procedure, a complete plasma volume was removed from the patient and was simultaneously replaced by a similar volume of 5% Human Albumin Grifols, which is a concentration of albumin similar to that found naturally in plasma. Preferably, plasma exchanges were performed through a double-lumen central line, although peripheral access was also permitted. After each procedure, blood count, calcium, activated partial thromboplastin time, prothrombin time and fibrinogen were monitored before patients were discharged.

Plasma Aβ40 and Aβ42 levels were determined at baseline, before and after each plasma exchange and once a month during 6 months of follow-up. On the other hand, CSF Aβ40 and Aβ42 were determined through a regular spinal tap at baseline, at the end of the plasma exchange period and at 3 and 6 months after the plasma exchange period. Determinations of plasma Aβ40 and Aβ42 were carried out with a sandwich-type ELISA test (b-amyloid [1-40] ELISA kit, Zymed, U.S.A. and Innotest b-amyloid [1-42] CE, Innogenetics, Belgium) originally commercialized for CSF determinations, following a protocol variation recommended by the manufacturer so that it could be more suitable for plasma determinations. It is important to note that at that moment a validated ELISA test for plasma Ab40 and Ab42 was not commercially available.

In addition to biochemical determinations, cognitive status was evaluated at baseline and at 3 and 6 months after the plasma exchange period through the Mini-Mental Status Examination (MMSE)86 and the Alzheimer’s Disease Assessment Scale, cognitive subscale (ADAS-Cog) examination.87

Finally, neuroimaging studies were also performed. Morphological assessments consisted of a magnetic resonance imaging (MRI) performed at baseline and at 3 and 6 months after the plasma exchange period to assess changes in the volume of the hippocampus, cingulate and other areas of interest. Functional neuroimaging assessments consisting of a single photon emission computed tomography (SPECT) were performed at baseline and at 6 months after the plasma exchange period to assess changes in brain perfusion (Neurogam™ software, Segami Corp., Columbia, MD, USA).88 A final follow-up visit was scheduled at 1 year after the enrollment.

This pilot study was performed in a single center (ACE Foundation – Catalan Institute of Applied Neurosciences, Barcelona, Spain). Before participating, each patient and/or close relative and/or legal representative signed the corresponding informed consent. Previously, the study had been approved by the local Ethical Committee and by the Spanish Ministry of Health. In addition, the study was conducted according to the Code of Ethical Principles for Medical Research Involving Human Subjects of the World Medical Association.

All patients fulfilled DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria for dementia and were diagnosed according to the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and the Alzheimer’s Disease and Related Disorders Association) criteria for possible and probable AD.89 All patients received a thorough clinical and neurological examination and a comprehensive neuropsychological evaluation including tests for general cognition, memory, language, perceptual and constructional abilities and executive functions. Complete blood analysis and neuroimaging studies were performed in all subjects to exclude other potential causes of dementia following the guidelines for the diagnosis of AD from the Study group on Behavioral Neurology and Dementia of the Spanish Neurological Society.

The patient population consisted of male and female subjects aged between 55 and 85 years, diagnosed with mild to moderate AD (NINCDS-ADRDA criterion) and an MMSE score between 20 and 24. Moreover, patients had to be on stable treatment with donepezil (6 months) and had to have an MRI or CAT scan performed within 6 months prior to participation, with absence of cerebral-vascular findings.

Pilot study results

Ten patients were included in this pilot study following a single-arm, open-label design. Seven out of the 10 patients underwent plasma exchanges with 5% Human Albumin Grifols. Out of these 7 patients, 3 underwent 5 plasma exchanges, 2 underwent 4 plasma exchanges and 2 underwent 3 plasma exchanges, during the planned 3-week period. The main reason why not all patients underwent the 6 plasma exchanges was that the hematology team responsible for the procedure followed the precautionary principle in this special patient population in relation with low coagulation parameters after each plasma exchange and with the mild anemia that is common in therapeutic plasma exchange programs. As will be stated later, based on the fact that the procedure was shown to be safe during the pilot study, an extension of the study was performed in which practically all patients underwent the 6 plasma exchanges within the planned 6 weeks.

Figure 2 shows the average plasma levels of Aβ40 and Aβ42 in the 7 patients that underwent plasma exchanges. Although there appears to be a slight variation of Aβ40 within the plasma exchange period, no clear pattern can be seen. On the other hand, the lack of a variation pattern is even more evident for Aβ42. At that moment, the investigators already realized that the lack of a reliable ELISA test for plasma Aβ determinations did not permit the adequate interpretation of plasma results. The method was improved during the study extension as shown later.

Figure 2. Mean plasma levels of Aβ40 and Aβ42 in the 7 patients that underwent plasma exchanges (PE) in the pilot study, determined at baseline, before and after each PE and once a month during 6 months of follow-up.

With respect to CSF Aβ40 and Aβ42, Figure 3 shows that both peptides follow a similar kinetics: a decrease is observed during the plasma exchange period followed by an increase after the plasma exchange period returning to baseline levels at 6 months of follow-up.

Figure 3. Mean cerebrospinal fluid levels of Aβ40 and Aβ42 in the 7 patients that underwent plasma exchanges (PE) in the pilot study, determined at baseline, at the end of the PE period and at 3 and 6 months after the PE period.

Figure 4 shows the changes from baseline of the scores corresponding to MMSE and ADAS-Cog tests measured at 3, 6 and 12 months after plasma exchanges. All scores (except obviously that measured at time 0) were assessed after the plasma exchange period (first 3 weeks). From the graphs it clearly appears that the cognitive status of the patients as measured by MMSE and ADAS-Cog remained stable after 1 year of follow-up.

Figure 4. Changes from baseline scores (average from the 7 patients of the pilot study) of the Mini-Mental Status Examination (MMSE) and the Alzheimer’s Disease Assessment Scale, cognitive subscale (ADAS-Cog) measured at 3, 6 and 12 months after plasma exchanges. For clarity, negative values of ADAS-Cog have been represented upwards.

Regarding MRI findings, the volume of the hippocampus measured at baseline, 3 and 6 months suggested a progressive volume increase. However, no clear pattern was observed for the posterior cingulate and the mid frontal gyrus (data not shown). With respect to functional neuroimaging (SPECT), 6 out of 7 patients showed a significant perfusion increase in the frontal and temporal areas (Fig. 5). At 6 months, statistical parametric mapping (SPM) analysis88 also showed a significant perfusion increase in both the frontal and temporal areas (data not shown).

Figure 5. Neurogam™ results from 2 representative patients with a different number of plasma exchanges (PE) performed: patient with 5 PE (left panels) had an improved perfusion and patient with 3 PE had an impaired perfusion (right panels). Upper and middle images: before and after treatment compared with a database of healthy subjects (hot colors [red and white] mean hyperperfusion and cold colors [blue and green] mean hypoperfusion). Bottom images: differences observed before and after treatment for each patient (hot colors [yellow, red and white] mean improved perfusion and cold colors [green, blue and purple] mean impaired perfusion).

Pilot study conclusions

One of the principal conclusions of this pilot (proof-of-concept) study was that treatment with 5% Human Albumin Grifols through a therapeutic plasma exchange regimen was feasible in mild to moderate AD patients, a patient population in which, to our knowledge, this has been the first time that this therapeutic approach has been carried out. However, an area of uncertainty remained with respect to the number of plasma exchanges to be performed since not all patients completed the 6-exchange cycle.

Relative to plasma levels of Aβ40 and Aβ42, it was clear that the lack of a reliable ELISA test for plasma determinations made the knowledge that could be extracted from the data obtained very obscure. However, for CSF Aβ40 and Aβ42, a clear pattern of variation was observed for both peptides suggesting that CSF Aβ may be mobilized with 5% Human Albumin Grifols used in the plasma exchanges.

Regarding the neurocognitive scores, the fact that there was a tendency to stabilization after 1 year of follow-up was interpreted as a promising clinical result, in accordance to European Medicines Agency (EMEA) guidelines on medicinal products for the treatment of AD.90 An obvious criticism is that since the study was open-label, the neurocognitive raters might have set up high expectations for the treatment leading to a bias in the cognitive assessment. Nevertheless, the objective of this pilot study was to uncover favorable tendencies which could be confirmed in subsequent randomized, controlled trials.

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