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.

Public Health Relevance

R01 PAR (PAR-11-100) - Project narrative (relevance) Down syndrome (DS) is a population highly enriched for people who will, with very high probability, develop Alzheimer's disease (AD). This raises the possibility that 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. With this proposal, the Alzheimer's Disease Cooperative Study (ADCS) aims to evaluate the first anti-amyloid immunotherapy for adults with DS in a Phase I, randomized, double-blind, placebo-controlled, clinical trial (ACI-24-1301) using the active immunotherapeutic ACI-24.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG047922-01
Application #
8750445
Study Section
Special Emphasis Panel (ZRG1-BBBP-V (55))
Program Officer
Ryan, Laurie M
Project Start
2014-08-15
Project End
2016-04-30
Budget Start
2014-08-15
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$826,451
Indirect Cost
$170,453
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093