Michael S. Rafii - US grants

DESCRIPTION (provided by APPLICANT): Down syndrome (DS), or trisomy 21, is caused by a triplication of chromosome 21. This chromosome encodes many genes including amyloid protein precursor (APP), which expresses ?-Amyloid (A?). Consequently, this results in excess production of A?. Virtually all people affected with DS show the neuropathological changes related to A? by age 40. The amyloid plaques found at autopsy in individuals with DS is identical to those found in individuals with Alzheimer's disease in the non-DS population. Therefore people with DS doubtlessly represent predictable AD cases. This raises the question as to whether individuals with DS could benefit from ongoing efforts to develop disease modifying anti- amyloid interventions for sporadic AD. And, in turn, provide important insights about the efficacy and timing of such interventions targeting sporadic AD in the general population. ACI-24 is a vaccine composed of a palmitoylated A? peptide anchored in liposomes and mixed with the monophosphoryl lipid A (MPLA) adjuvant. ACI-24 induces antibodies against A? and thereby lowers soluble A?. In addition, ACI-24 induces an anti-A? antibody response that is largely independent from T- cell activation and, therefore, is expected to exert a favorable safety profile As a proof-of-concept study, Ts65Dn mice have been immunized with ACI-DS-01 (murine equivalent of ACI-24), and a robust antibody response and an improvement in memory capacity has been observed. This work has demonstrated the beneficial effect of ACI-24 as anti-A? vaccine for the treatment of cognitive decline in DS. The preclinical safety data as well as the ongoing Phase I/II clinical trial in AD indicate a favorable safety profile for ACI-24. The propose study will investigate the safety, tolerability, as well as immunogenicity of the ACI-24 vaccine in a Phase I clinical trial in adults with DS aged 35-55. Effects on cognitive function and AD biomarkers will be secondary endpoints. This project will be testing the first immunotherapy for the treatment of Alzheimer's disease in Down syndrome.

The overall aim of the ADCS is to advance research in the development of interventions that might be useful for treating, delaying, or preventing AD, particularly interventions that might not be developed by industry. In particular, the ADCS has focused on instrument and trial methodology, and the testing of potential therapeutics that might not otherwise be studied by the pharmaceutical industry. For the coming grant cycle, the ADCS will continue its efforts to advance therapeutics through controlled clinical trials, development o novel instruments and trial designs, recruitment efforts (with particular attention to recruitment f minority subjects). The organization will continue its recent emphasis on collaboration and data sharing. Specific Aims: Aim 1: Test interventions to Improve cognition, slow the rate of decline, or delay/prevent the onset of AD. Three of the four projects in this application aim to slow disease progression. Aim 2: Test an intervention to ameliorate behavioral symptoms. We will extend promising early results supporting an adrenergic approach amelioration of behavioral symptoms with a multicenter trial of prazosin. Aim 3: Design new instruments for use in clinical trials. For the present cycle, we have incorporated instrument development into our largest project, the A4 trial. Aim 4: Develop novel and innovative approaches to AD clinical trial design. The A4 trial utilizes a new trial design to test a leading intervention at the earliest feasible stge of disease, preclinical AD. Aim 5: Develop novel and innovative approaches to AD clinical trial analysis. The Biostatistics Core will continue efforts to advance analytical approaches to AD trial design. Work will continue on optimal modeling of longitudinal data, including novel methods to link diverse datasets. Aim 6:.Expand the range of individuals studied in AD studies to include at-risk individuals and those with MCI. The ADCS has focused its methodological research on early-stage trials, and for this cycle, the two largest projects target preclinical AD and mild cognitive impairment. Aim 7: Enhance the recruitment of minority groups into AD studies. For the coming cycle, the ADCS Minority Recruitment Core will expand outreach efforts, and we will require sites to meet minority enrollment targets in our two largest trials.

PROJECT SUMMARY/ABSTRACT The discovery that individuals with Trisomy 21, or Down syndrome (DS) have neuropathological features identical to those with sporadic Alzheimer's disease (AD) played a critical role in the identification of the amyloid precursor protein gene on chromosome 21 supporting the amyloid cascade hypothesis. People with DS have a lifetime risk for dementia in excess of 75% and comprise the world's largest population of genetically-determined AD. Just as studying DS helped identify the role of amyloid precursor protein mutations in AD pathogenesis, it is also likely to inform us of the potential benefit of manipulating the amyloid pathway on treatment outcomes in AD. It is critically important to the DS population and to the AD therapeutics field to conduct clinical trials, particularly those targeting amyloid accumulation, in individuals with DS. With this application, we propose to utilize the existing depth and breadth of expertise of the NIA-funded Alzheimer's Clinical Trial Consortium (ACTC) to conduct AD clinical trials in adults with DS across performance sites with expertise in DS including the Alzheimer's Biomarker Consortium for Down Syndrome (ABC-DS). As part of an NIH award received last year, we established the ACTC-DS network which includes working groups comprised of leaders from ACTC, ABC-DS and the European Horizon21 DS network to develop the collaborations, infrastructure and plans required to conduct AD clinical trials in DS. During the proposed R61 `Trial Readiness Phase' of the present project, in Aim 1, we will enroll 120 adults with DS (ages 35-55) across 15 sites into a trial ready cohort (TRC) to collect outcome measures and biomarkers harmonized with those being collected in the ongoing ABC- DS study (n = ~400). In Aim 2, we will determine the relationships between cognitive measures and AD biomarkers to identify endpoints for clinical trials that best reflect disease progression. During the R33 `Clinical Trial' phase, for Aim 3, we propose to implement a phase II randomized, double-blind, placebo-controlled trial to evaluate the safety and tolerability of a promising anti-amyloid therapeutic among individuals the TRC. In Aim 4, we will determine the impact of this agent on biomarker evidence of disease modification. Fundamentally, this project will serve to bring AD therapies to the DS population by leveraging the infrastructure of ACTC and incorporating the experience and expertise of the ABC-DS and Horizon21 networks. Beyond the proposed trial, this will establish the means and methods to conduct future therapeutic trials in this population. The potential impact of this approach on improving the lives of adults with DS as well as the general population cannot be overstated.

PROJECT SUMMARY/ABSTRACT Down syndrome (DS) is the most common genetic cause of intellectual disability, with virtually all DS individuals having AD by age 60. Despite exciting advances over the past 20 years in our understanding of DS and how genetics confer susceptibility for AD, there have been few clinical trials to treat AD in the DS population (DS-AD) and currently no means to clinically impact disease progression. We hypothesize that the biological makeup of DS-AD is as heterogeneous as the sporadic AD population and that identifying specific subsets of DS-AD for particular treatments will yield meaningful therapeutic responses. We propose to test a validated biomarker for sporadic AD, our established proinflammatory endophenotype analysis. This analysis will allow for an understanding of differences in immune signaling between DS-AD individuals and how this may impact anti- inflammatory effects on AD biomarkers. For this study we will leverage biobanked samples from the previously completed Phase 3 clinical trial, ?Vitamin E in Aged Persons with Down Syndrome (NCT00056329).? For our proposed work we will employ high throughput proteomics on native plasma and exosome subpopulations to validate new techniques and develop a framework for designing better therapeutic trials for DS-AD