Stockholm: Science Smorgasboard at Biannual Meeting

07 Jun 2012

The 12th International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy took place May 9-12 in the Swedish Capital. Organized by Agneta Nordberg, Karolinska Institute, Stockholm, and Ezio Giacobini and Gabriel Gold from the University of Geneva, Switzerland, this meeting had something for nearly everyone’s palate, from basic biology to preclinical drug discovery and on through to diagnostic and treatment strategies. In the plenary session, on the health challenges of AD for the 21st century, Laura Fratiglioni, from the Karolinska, addressed the question of whether the disease is preventable.

The answer is not clear, but, Fratiglioni reminded the audience that 40 percent of nonagenarians do not have dementia. Why? Looking through data from the Kungsholmen Project, a longitudinal, population-based study of aging that started in 1987, Fratiglioni found that about half of the people who develop dementia have one or more comorbidities. They were less active, encumbered with higher cardiovascular disease burden, and were less well educated or involved in simpler work than those who remained dementia free. Acknowledging these well-studied risk factors, Fratiglioni said that tackling those could go a long way toward prevention (see ARF related news story). In fact, Fratiglioni hinted that the incidence of AD may be falling because people are now aging with less vascular disease than some years ago. Researchers at the meeting thought this could be a major shift. “The arguments are compelling and if true indicate a much bigger effect than you can imagine any drug to have,” Lon Schneider, University of Southern California, told Alzforum. While Schneider thinks it is plausible that age-specific incidence could be falling, he noted that data supporting the idea is still lacking. Fratiglioni told Alzforum that she plans to submit data from the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K) project for publication soon.

Nevertheless, the world faces a growing dementia problem as life expectancy increases globally. Intervention studies have begun to test the idea that reducing risk factors can prevent dementia, noted Miia Kivipelto, also from the Karolinska. For example, the PreDiva—or Prevention of Dementia by Intensive Vascular Care trial —being run by Willem van Gool and colleagues at the University of Amsterdam, in the Netherlands, uses nurse intervention to limit vascular disease burden (see Richard et al., 2009). In France the Multidomain Alzheimer Preventive Trial or MAPT (see Gillette-Guyonnet et al., 2009) led by Bruno Vellas and colleagues at the University of Toulouse tests whether a dietary (omega 3 fatty acids) and/or a multidomain intervention that tackles metabolic and vascular risk factors can reduce dementia incidence.

For her part, Kivipelto summarized the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). This two-year study will test if a multidomain lifestyle intervention can reduce cognitive decline.

FINGER recruited 60-77 year-olds from a national population-based non-intervention study (FINRISK). The 1,200 people recruited receive placebo or an intervention covering four domains: nutrition; exercise; cognitive training; and monitoring and management of metabolic and cardiovascular risk factors. Control subjects receive advice but no intervention, said Kivipelto. The primary outcome for the trial is cognitive impairment assessed with the Neuropsychological Test Battery, and Stroop and Trail Making tests. Preliminary results from the first year of the trial that suggest the intervention reduces body weight and body-mass index, and lowers total and LDL-cholesterol. Oral glucose tolerance tests hint at a positive trend toward better metabolism. No cognitive data is available yet, Kivipelto said.

Kivipelto said that data from FINGER, PreDIVA and MAPT could serve as a basis for larger multinational trials. The Finnish, Dutch and French trials are already networking through the European Dementia Prevention Initiative, which was launched in April 2011 in Stockholm.

Can such intervention studies really reduce the risk of dementia? Kivipelto and others have devised risk scores for dementia based on modifiable factors such as high blood pressure, serum cholesterol, and obesity (see ARF related news). As Kivipelto suggested in her presentation, those scores suggest that a 50-year old male with a poor cardiovascular profile and a 16 percent risk of becoming demented by age 70 could quench his risk to seven percent by lowering serum cholesterol and blood pressure, and even to two percent by taking up exercise and losing weight. Only intervention studies can determine whether such predictions turn out to be true.—Tom Fagan.

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Stockholm: New Strategies for Immunotherapy

08 Jun 2012

Immunotherapy continues to be a major therapeutic strategy for Alzheimer’s disease, and more recently for other neurodegenerative diseases as well. At the 12th International Stockholm/Springfield Symposium on Advanced in Alzheimer Therapy, researchers discussed some new immune-based approaches for therapy, including those capitalizing on the body’s own antibodies for passive immunotherapy and novel antigens for active vaccination.

Andreas Muhs from the company AC Immune, Lausanne, Switzerland, have adopted the latter strategy. Muhs and colleagues develop a lipospome-based antigens. The researchers are interested in targeting toxic forms of tau. As Muhs noted in his talk, there is now evidence that tau, a normally cytosolic protein, finds its way into the extracellular space from where toxic forms of the protein may spread to healthy cells (see related ARF news). This makes targeting extracellular tau a potential valuable strategy, said Muhs.

Their vaccines use synthetic peptides are coupled to a linker that is attached to a lipid bilayer (see Hickman et al., 2011). The linkers can be designed to make the liposome aggregate, boosting immunogenicity, while the use of synthetic peptides rather than whole proteins increases the specificity of the vaccine. Muhs and colleagues used this strategy to vaccinate six to nine month old mice with liposomes carrying a fragment of human tau containing a phosphorylated serine 396, which is found in paired helical fragments of tau. The antigen generated robust immune responses in wild-type and tau P301L transgenic animals. The antibodies recognized PS396 forms of tau but not un-phosphorylated forms of the protein. In the P301L animals, the vaccination reduced both soluble and insoluble tau in the brain and delayed the emergence of motor problems (poor grip strength) seen in this animal model.

A company called AFFiRiS AG, in Vienna, Austria, is also pursuing novel antigens. Markus Mandler explained that the company’s "affitopes" are short antigens that mimic other epitopes without sharing any primary amino acid structure. An Aβ affitope would mimic the Aβ secondary structure, for example, without having Aβ sequences. Such an epitope could then elicit an immune response against itself and Aβ. Mandler explained that the advantages are specificity (affitopes would not elicit an antibody response to native proteins or homologs) and side-stepping auto-reactive T-cell responses, which can lead to dangerous neuroinflammatory responses, as happened with the first Aβ vaccine tested in clinical trials (see related ARF news).

Mandler and colleagues have developed affitope vaccines for both Alzheimer’s and Parkinson’s diseases. Achim Schneeberger, also from AFFiRiS, reported on premilinary clinical data using two AD01 and AD02 affitopes that mimic the N-terminus of Aβ. In these Phase 1 studies, patients with mild to moderate AD (MMSE 16-26) received four monthly injections of the vaccine. Patients on AD02 got another booster shot at week 20. The patients developed antibodies peaking around week 10, and increasing further after the booster, said Schneeberger. He showed fluorescent-activated cell sorting data to demonstrate that the antibodies did not react with APP.

Though this was a small trial, the results look encouraging, said Schneeberger. Patients whose MMSE was above 20 at the start of the trial remained stable on the MMSE and performed better than controls in activities of daily living, functional scales, and in the neuropsychiatric inventory. The responses seemed to correlate with the titer of the antibody against Aβ aggregates, suggesting some cause and effect.

Mandler also reviewed preclinical data on PD01, an affitope that mimics an α-synuclein sequence. This antigen induces antibodies that recognize α- but not β-synuclein, said Mandler. The company tested PDO1 in mice overexpressing human synuclein under control of the PDGF promoter. These animals are more model of Lewy body dementia than Parkinson’s disease. PD01 reduced soluble and insoluble α-synuclein in whole brain extracts from these mice and also in the cerebral cortex and hippocampus as viewed by immunohistochemistry. Vaccinated mice retained twice as many dendrites as controls and about fifty percent more neurons. They outperformed controls in the Morris water maze test of spatial learning. The antibodies induced by PDO1 somehow get across the blood brain barrier into the brain, said Mandler, because they turn up in neuronal lysosomes and in the perivascular space. AFFiRiS is testing PD01 in a Phase 1 clinical trial.

Another new approach, taken by Roger Nitsch, Christoph Hock, and colleagues at Neurimmune, Schlieren, Switzerland, capitalizes on the body’s own immune defenses against amyloidogenic proteins. Hock and colleagues isolated antibodies from circulating B cells of healthy centenarians and screened for those with high-affinity binding to Abeta aggregates (see ARF related news). In Stockholm, Nitsch reported that a similar strategy, termed reverse translational medicine, yielded an antibody, NI-204A, against superoxide dismutase 1 (SOD1). SOD aggregates in both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). NI-204A binds to the spinal cord of transgenic mice expressing a mutant (G93A) form of SOD1 that causes familial ALS, reported Nitsch. The antibody also binds to epitopes in the spinal cord of 80 percent of ALS patients. The frequency most likely reflects the heterogeneity of the disease, said Nitsch.

Can this antibody work as a therapeutic? By pumping the antibody into the brain ventricles of transgenic SOD mice over their entire lifespan, Nitsch and colleagues stemmed the loss of spinal cord motorneurons. The treated animals had twice as many neurons as transgenic controls, though this was not quite enough to bring them back to normal function, said Nitsch. For that, another doubling of motoneurons would be required. Nevertheless, the treated animals did reap some benefits. As they aged they gained more body weight than untreated SOD mice, and they developed stronger grip. They also survived longer than controls, though only by about 20 days. Nitsch said that Neurimmune plans to test NI-204A in the clinic and that it is turning the reverse translational medicine strategy to other neurodegenerative diseases, as well. Hock reviewed preclinical data on the BIIB037 Abeta antibody that the company previously presented (see related ARF news).

Last but not least, Daniel Michaelson from the University of Tel Aviv, Israel, outlined a monoclonal antibody (mAb) approach for reining in potential toxic functions of ApoE4. To make these antibodies, Michaelson used immune cells from ApoE-deficient mice that had been vaccinated with a peptide containing the ApoE4 allele (an arginine at position 112). He obtained several cell lines producing mAbs that, by a variety of tests (ELIAS, Western blot, immuniprecipitation and immunohistochemistry), react with ApoE4 but not with ApoE3. In mice that have their endogenous ApoE replaced with the human ApoE4, these mAbs reduce the apolipoprotein in the CA3 layer of the hippocampus and also toned down the amount of phosphorylated tau as judged using the AT8 antibody. Interestingly, the mAbs did not prevent accumulation of Aβ42 in the hippocampus or deficits in the presynaptic glutamate transporter VGlut1. Michaelson did not know why the mAbs reduced tau but not Aβ. It may be due to bioavailability, he suggested, but acknowledged that there is debate in the field as to whether loss or gain of function underlies ApoE effects in AD and that Abeta effects may be due to the former. He told Alzforum that he believes boosting ApoE may help in people who have no E4 allele, but that targeting ApoE4 for removal would help those who carry the risk allele.—Tom Fagan.

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Stockholm: Therapeutics Roundup—Some New, Some Not So Much

15 Jun 2012

Are AD therapeutics about to go viral? NeuroPhage Pharmaceuticals, a small startup company, is banking that viral capsids will break up aggregates of Aβ and other amyloidogenic proteins. Company researchers outlined their strategy at the 12th International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy, which took place in the Swedish capital from 9-12 May 2012. While novel immunotherapies also made a splash at the meeting (see also ARF related news story), interest in some older treatments for Alzheimer’s disease resurfaced as well. Researchers debated the virtues of combining acetylcholinesterase blockers with monoamine oxidase inhibitors; new evidence emerged on vitamin B’s punch to slow neurodegeneration in people with high homocysteine levels; and a hypertension drug found new life as a potential AD treatment. Finally, scyllo-inositol, a compound that missed its primary endpoint in a recent trial, hung on tenaciously as a potential treatment for neuropsychiatric symptoms.

Richard Fisher from NeuroPhage based in Cambridge, Massachusetts, said that his company’s strategy is to capitalize on the interaction of the filamentous M13 phase with Aβ. M13 may be better known to researchers for its versatility in cloning genes, but researchers previously found that it binds to and disrupts amyloid fibrils. Fisher detailed preclinical data to show that NPT001 and NPT002, proprietary derivatives of M13, do the same and also prevent Aβ toxicity in cell culture assays. In vivo, these capsids co-localized with and reduced plaques in mouse models of AD. A bilateral injection of phage into the hippocampus kept plaques at bay for six weeks, and the mice performed better in novel object recognition and spontaneous alternation tasks. Curiously, while the phage reduced plaque burden by half, suggesting Aβ was solubilized, interstitial Aβ did not change. Fisher said he is unsure why, but thinks that the phage and Aβ become tightly complexed.

Fisher acknowledged challenges in translating this approach into humans, not least being how to get sufficient numbers of phage particles into the brain. Intrathecal administration may be the answer. Fifty percent of a bolus of viral particles injected intrathecally into monkeys made it into the brain, he said. Assuming the company can overcome the creep factor of having phage infused directly into brain, NeuroPhage plans a Phase 1 trial in AD patients for 2013. The company will use amyloid PET imaging to test if NPT002 can break down plaques. Other scientists frequently mix the words "intrigued" and "out there" when discussing NeuroPhage’s research. It grew out of Beka Solomon’s early work on filamentous phages in AD (see ARF related conference story); indeed, Solomon’s son Jonathan is president and CEO of the company.

Another plaque buster, scyllo-inositol (aka ELND005), was developed by Elan Pharmaceuticals in collaboration with partner Transition Pharmaceuticals (see ARF related news story). In a Phase 2 clinical trial, the drug failed to significantly improve cognition or function in patients with mild to moderate AD (see ARF related news story). The compound did reduce Aβ in cerebrospinal fluid, and the companies claimed that exploratory analyses suggested improved clinical endpoints in some patients. With these results, they moved the compound into a Phase 3 trial where the two highest doses (1 g and 2 g twice daily) caused such serious adverse events that they were dropped (see ARF related news story). At a mini-symposium in Stockholm, an entirely new story emerged. Apparently, low doses of scyllo-inositol may benefit AD patients not by blocking Aβ aggregation, but by reducing myoinositol in the brain.

Elan’s Gene Kinney recounted how falling myoinositol levels were discovered when company researchers used NMR to confirm scyllo-inositol had made its way into the brain. The researchers noticed that, as brain scyllo-inositol rose, its myo-isoform fell. Going back to animal models, they found that the myo isoform dropped by as much as 70 percent when the animals imbibed drinking water laced with scyllo-inositol. Why is this important? Previously, researchers had reported elevated brain myoinositol in patients with AD, Down's syndrome, and bipolar disorder, said Kinney (see Miller et al., 1993). More recently, a group in Japan correlated elevated brain myoinositol with behavioral and psychological problems in AD patients. Lithium, which has been used for many years to treat neuropsychiatric disorders, may work in part by reducing myoinositol. In fact, a 30 percent reduction of myoinositol is predictive of lithium efficacy, said Kinney. By reducing myoinositol, could scyllo-inositol treat neuropsychiatric symptoms in AD patients?

Susan Abushakra, also from Elan, reported that the 250 mg dose of scyllo-inositol drove down brain myoinositol by about 40 percent. She also said that post-hoc analysis of the Phase 2 trial indicated that fewer neuropsychiatric symptoms emerged in patients on drug compared to those on placebo. Pierre Tariot, Banner Health, Phoenix, Arizona, dove into that analysis in depth. While patients on 250 mg scyllo-inositol declined at the same rate on the neuropsychiatric inventory (NPI) over the 78 weeks of the trial as those on placebo, Tariot considered it worthwhile to specifically investigate the emergence of new symptoms during the course of the treatment. He looked for an increase from a score of zero on two or more of the test items in the NPI; these include aberrant motor activity, agitation/aggression, anxiety, apathy, appetite change, delusions, disinhibition, dysphoria, euphoria, hallucinations, and irritability/lability. He found that 75 percent of trial participants with mild AD on placebo had two emerging symptoms as opposed to 50 percent of patients on 250 mg scyllo-inositol. Looking at single NPI items, the researchers noted that the drug seemed to stem emergence of depression, appetite changes, agitation, and anxiety. Tariot also found a correlation between decline in brain myoinositol and suppression of these behaviors.

Some researchers who attended the symposium were unsure what to make of this. Competition with sodium/myoinositol transporters offers a plausible explanation for how scyllo-inositol lowers the myo isoform in the brain, but how that translates into a behavioral effect was anybody’s guess. Some asked if changes in inositol-phosphate signaling cascades are responsible. Abushakra said that Elan was looking into that. She also said that reductions in osmotic pressure might be at play; myoinositol happens to be a major osmolyte in the brain. On that note, Constantine Lyketsos, Johns Hopkins University, Maryland, reported that patients who responded to the treatment had less cerebroventricular enlargement, which may be related to osmotic changes.

Further analysis suggested that patients who benefited from the drug had milder cognitive deficits and lower tau in the cerebrospinal fluid at baseline than those who did not, noted Lyketsos (see also ARF related news story). This will be helpful in thinking about further clinical development, he suggested. Whether Elan will pursue the drug is unclear. Tariot said scyllo-inositol was under consideration as a potential prevention drug. Abushakra said the company is weighing its options.

Ladostigil is another treatment that might relieve neuropsychiatric symptoms, reported Marta Weinstock, Institute of Drug Research in Jerusalem, Israel. This drug is a pro-drug derivative of rivastigmine, an acetylcholinesterase inhibitor Weinstock helped develop. In the brain, cholinesterases metabolize ladostigil to generate a monoamine oxidase (MAO) inhibitor that boosts levels of dopamine, noradrenalin, and 5-hydroxytryptamine. Weinstock said she expects the drug would reduce anxiety, apathy, and depressive symptoms in AD patients. Ladostigil has just finished a Phase 2 clinical trial sponsored by Avraham Pharmaceuticals, Yavneh, Israel. In this multicenter, double-blind trial, people with mild to moderate AD (MMSE 14-24) took 80 mg of ladostigil twice daily for six months. Cognition and safety were the primary outcomes with behavioral and psychiatric evaluations as secondary measures. The results are expected in the last quarter of 2012.

Weinstock reviewed preclinical data that suggests this drug might help dementia patients. In addition to its MAO and cholinesterase activity, the drug and its metabolites protect cells against oxidative stress and nitric oxide, she said. She believes that the compounds prevent opening of the mitochondrial transition pore, which can trigger apoptosis. In microglial cultures, ladostigil and metabolites seem to tone down release of nitric oxide and inflammatory cytokines. She showed that the drug protected rats against age-related decline in novel object recognition and spatial memory. A three-year Phase 2 trial of low-dose ladostigil (10 mg) in people with mild cognitive impairment is currently recruiting subjects.

Moussa Youdim, Technion-Israel Institute of Technology, Haifa, Israel, described a different type of MAO inhibitor hybrid that also acts as an iron chelator. Youdim noted that iron chemistry creates oxidative stress, and that iron accumulation in the brain has been linked to AD and other neurodegenerative diseases. Amyloid precursor protein (APP) mRNA contains an iron response element that might drive APP synthesis. Youdim reported that several compounds with MAO inhibitor/iron chelator properties reduced APP and β-secretase fragments of APP in 10-month-old APP/PS1 transgenic mice, and attenuated soluble Aβ and amyloid plaque burden.

A different potential therapy that has returned mixed results in the past is vitamin B. David Smith, University of Oxford, England, co-leads the VITACOG trial that indicated B vitamins slow brain atrophy and reduce cognitive decline in people with mild cognitive impairment who also have high plasma homocysteine, a neurotoxin (see ARF related news story). In Stockholm, Smith presented voxel-based morphometry data for a detailed look at atrophy changes. He reported that over the course of the two-year trial, vitamin B slowed atrophy in most areas of the brain examined, including the hippocampus, fusiform gyrus, precuneus, and middle and inferior temporal gyri. Smith said that, overall, the treatment slowed atrophy by about 50 percent. He said the results are evidence of a disease-modifying effect, claiming that, while the treatment may not cure AD, it may prevent it.

Lastly, Giulio Pasinetti from Mount Sinai School of Medicine, New York, discussed the possibility of treating AD with drugs previously approved for entirely different conditions. He is planning a pilot trial to test if carvedilol, an anti-hypertensive, can improve cognition. This will be a six-month, single-site trial recruiting 50 AD patients. Pasinetti and colleagues singled out carvedilol after screening previously approved drugs for Aβ-lowering activity in mice. CRND8 transgenic mice taking 7.5 mg of the drug daily perform better in novel object recognition tests of learning and memory, had reduced Aβ in the brain, and showed improved synaptic plasticity, said Pasinetti. In response to questions, he said he does not know how carvedilol works in this context. Its hypertensive action seems irrelevant because blood pressure in the mice did not change at the doses used. Preliminary evidence suggests a metabolite of the drug may interact with Aβ, he said.—Tom Fagan.

International Stockholm / Springfield Symposium on Advances in Alzheimer Therapy, 2012

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Stockholm: Science Smorgasboard at Biannual Meeting

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