Results from a Phase II Study to Assess the Clinical and Immunological Activity of AFFITOPE® AD02 in Patients with Early Alzheimer's Disease.

OBJECTIVES: The primary objective of this clinical trial was to assess the clinical activity of various doses and formulations of AFFITOPE® AD02 following its repeated s.c. administration to patients with early Alzheimer´s disease (AD), based on the evaluation of cognitive and functional domains. DESIGN: It was designed as a randomized, placebo-controlled, parallel group, double blind, multicenter phase II trial with 10 regular outpatient visits and 6 telephone interviews. SETTING: The trial was performed at 32 sites in six countries. PARTICIPANTS: A total of 332 patients were enrolled and 265 patients completed the trial in 3 treatment groups with AD02 and 2 control groups with aluminum oxihydroxide, here named IMM-AD04. Patients were randomly assigned to 5 groups: two doses of IMM-AD04, 25µg AD02 (in two different formulations) and 75µg AD02. INTERVENTION: At months 0, 1, 2, 3, 9 and 15, each patient received a single s.c. injection of the corresponding preparations of AFFITOPE® AD02 or the control, IMM-AD04. MEASUREMENTS: Co-primary efficacy outcomes included a measure of cognition (adapted AD Assessment Scale cognitive [aADAS cog]), and a measure of function (adapted AD Cooperative Trial Activities of Daily Living [aADCS-ADL]). A primary composite score was the sum of these two scores. RESULTS: Treatments were generally well tolerated and adverse events (AEs) were seen at similar rates across all treatment groups, with the exception that more injection site reactions were seen in the groups with a higher level of adjuvant. None of the AD02 groups showed a benefit over the IMM-AD04 controls for primary or exploratory efficacy outcomes. The control groups differed on aADCS-ADL and therefore couldn't be pooled (p=0.039). Unexpectedly, the 2mg IMM-AD04 showed statistically significant effects over the other groups on several clinical outcomes including: aADAS-cog, aADL, Composite, ADAS-cog, CDR-sb, and QOL-AD Caregiver as well as two biomarker outcomes: right and total hippocampal volume (all p<0.05). 48% of patients in the IMM-AD04 2mg group had no decline in the composite outcome over 18 months compared to 17%-31% in the other groups, which is consistent with historical placebo groups. CONCLUSION: No significant treatment effects were seen for the investigational compound AD02. However, the IMM-AD04 2mg group showed statistically significant effects over all other groups on several clinical outcomes as well as a slowing of decline on right hippocampal volume. The data support further development of IMM-AD04 as a disease modifying agent in line with EMA/FDA definitions.

Vaccination for Parkinson's disease.

Idiopathic Parkinson's disease (PD) is, like other neurodegenerative diseases such as Alzheimer's disease (AD) considered a proteinopathy. Thus, a disease that is driven by the accumulation and aggregation of misfolded proteins, in case of PD α-synuclein (aSyn) is incriminated. Accordingly, removal of aSyn is assumed of having the potential to modify the course of the disease. Both active and passive aSyn targeting immunotherapy were found to modify disease in mice overexpressing human aSyn and recapitulating various aspects of synucleopathies. Translating immunotherapy to humans needs to consider the issue of potential autoimmunity. PD vaccines developed by AFFiRiS integrate the safety concept as applied for the company's AD vaccine candidates. This includes the use of short antigens, precluding activation of aSyn-specific T cells and, thus, cellular autoimmunity. Moreover, the selection of AFFITOPES® for clinical development is based on the principle of exclusive aSyn reactivity of vaccine-induced Abs excluding crossreactivity to ß-synuclein (bSyn), which is ensured by the AFFITOME® platform technology. PD01, the first in class aSyn vaccine developed by AFFiRiS is about to enter the clinical phase of development.

Development of AFFITOPE vaccines for Alzheimer's disease (AD)--from concept to clinical testing.

Based on the notion that cerebral accumulation of certain Abeta species is central to AD pathogenesis and endowed with the knowledge that emerged during clinical testing of the first human Alzheimer vaccine, AN1792, we designed a new generation of Alzheimer vaccines. Rather than relying on full-length Abeta itself or fragments thereof, AFFITOPE vaccines use short peptides, mimicking parts of the native Abeta sequence, as their antigenic component. The technology created to identify these peptides, termed AFFITOPE-technology, at the same time provides the basis for the multi-component safety concept realized in AFFITOPE vaccines. First, as they are nonself, AFFITOPES don't need to break tolerance typically established against self proteins. This allows us to use aluminium hydroxide, the agent first approved as immunological adjuvant for human use and, thus, exhibiting an excellent safety profile. Second, AFFITOPES employed in Alzheimer vaccines are only 6 amino acids in length, which precludes the activation of Abeta-specific autoreactive T cells. Third, and above all, the AFFITOPE technology allows for controlling the specificity of the vaccine-induced antibody response focusing it exclusively on Abeta and preventing crossreactivity with APP. In a program based on two AFFITOPES allowing neoepitope targeting of Abeta (free N-terminus), this approach was taken all the way from concept to clinical application. Early clinical data support the safety concept inherent to AFFITOPE Alzheimer vaccines. Further clinical testing will focus on the identification of the optimal vaccine dose and immunization schedule. Together, result of these trials will provide a solid basis for clinical POC studies.

FGF signaling is necessary for the specification of the odontogenic mesenchyme.

Tooth development is initiated by signals from the oral ectoderm which induce gene expression required for tooth development in the underlying mesenchyme. In this study, we have used Su5402, an inhibitor of FGF receptor signaling, to analyze the requirement of FGF signaling during early tooth development. We show that FGF signaling is necessary for expression of Pax9, a transcription factor required for development of all teeth, in prospective incisor and molar mesenchyme until E11.0. Expression of the LIM homeobox gene Lhx7 also requires FGF signaling until E11.0 whereas expression of its homologue Lhx6 and the homeobox transcription factor Barx1 already becomes independent of FGF signaling at E10.75. In contrast, ectodermal expression of several genes thought to be important for tooth development was unaffected by the block of FGF signaling. Finally, we show that expression of the TGFbeta antagonist Dan in prospective tooth mesenchyme requires ectodermal signals and can be induced by FGF-soaked beads but is maintained in mandibular explants in the absence of FGF signaling. Together, these results demonstrate that FGF signaling is required for development of both molar and incisor teeth and suggest that specification of tooth mesenchyme involves at least two FGF-dependent steps.

Mechanisms of simultaneous color induction.

A new method of measuring simultaneous contrast, or chromatic induction, is introduced and used to test the hypotheses that induction results from either multiplicative or subtractive interaction of either like receptors or like second-stage, opponent mechanisms. Predictions derived from these hypotheses do not predict the outcome of the experiments as well as the traditional notion that induced colors are in the direction complementary to the inducing color with respect to the test color. We conclude that simultaneous contrast is a consequence of interaction within higher-level chromatic mechanisms.

Higher order color mechanisms.

Evidence supporting the existence of higher order color mechanisms, that is, ones beyond the previously identified second stage mechanisms is presented. This evidence includes a reanalysis of the data of Krauskopf et al. [Vision Res. 20, 1123-1131 (1982)] on the desensitizing effects of viewing chromatically modulated fields, new experiments on a generalized version of the "transient tritanopia" experiment of Mollon and Polden [Phil. Trans. R. Soc. Lond. 278, 207-240 (1977)] and results on the relationship between discrimination and detection of brief color changes.

Temporal frequency discrimination above threshold.

Temporal frequency discrimination was measured above threshold with a two-alternative spatial forced-choice procedure. Stimuli were two 1 deg homogeneous fields modulated around a mean luminance of 3.7 log trolands. Observers determined which of the two stimuli was modulated at a higher frequency. To avoid differences in apparent modulation depth as a cue for discrimination, all stimuli were matched in apparent modulation depth to an 11 Hz standard that was 0.5 log units above its threshold. Adaptation, caused by repeated presentation of suprathreshold stimuli, was avoided by using a 15 sec inter-trial interval. The relative difference thresholds (delta f/f) were a non-monotonic function of frequency. Discrimination was best near 1.5, 4.0 and 30.0 Hz (delta f/f = 0.08) and worst near 20.0 Hz (delta f/f = 0.50). Control experiments showed that the improvement in discrimination beyond 20.0 Hz was not an artifact of mismatches in apparent modulation depth. These results demonstrate the existence of multiple channels sensitive to different ranges of temporal frequency.

A three channel model of temporal frequency perception.

This paper derives the constraints on a set of channels that would be consistent with the results of several experiments on the temporal properties of the visual system, and it describes a specific set of channels that meet these constraints. Data on simultaneous detection and discrimination require a minimum of three channels. Temporal frequency discrimination at and above threshold constrain the bandwidths and locations of the channels. The shape of the temporal modulation sensitivity function constrains their sensitivities. The functions that meet these constraints are similar to those derived from masking data, and they can account for data on flicker matching, notch losses in modulation sensitivity, and changes of perceived temporal frequency with changes of modulation depth.

Binocular flicker appears faster than monocular flicker.

Observers adjusted the frequency of an auditory click to match the apparent flicker rate of a sinusoidally modulated visual display. Matches made for binocularly viewed flicker were nearly twice those for monocularly viewed flicker but only at high rates of temporal modulation.

Obras de desag³es cloacales de El Colorado, provincia de Formosa; colector general, estación elevadora, establecimiento depurador, descarga y obras complementarias

Contiene las normas de diseño e información técnica del proyecto. El estudio diseña las obras proyectadas para un plazo de 30 anos, previendo para el ano 2010 una población de 9,734 habitantes para la localidad. El proyecto se ha diseñado en dos modulos a realizarse en dos etapas; cumplida la primera, quedaran cubiertas las necesidades para una población de 5,500 personas

Obras de desag³es cloacales de El Colorado, provincia de Formosa; colector general, estación elevadora, establecimiento depurador, descarga y obras complementarias

Contiene las normas de diseño e información técnica del proyecto. El estudio diseña las obras proyectadas para un plazo de 30 anos, previendo para el ano 2010 una población de 9,734 habitantes para la localidad. El proyecto se ha diseñado en dos modulos a realizarse en dos etapas; cumplida la primera, quedaran cubiertas las necesidades para una población de 5,500 personas