SBIR-STTR Award

The beta-amyloid peptide and the cerebral plaques that it forms are likely to be either the direct or indirect cause of Alzheimer's disease (AD). This peptide is produced in both the brain and peripheral tissues by cleavage from a common cell-surface precursor protein. Soluble beta-amyloid exists free in the blood and cerebrospinal fluid while "insoluble" aggregates are deposited in the brain as amyloid plaques. The soluble and insoluble forms of beta-amyloid present within Alzheimer's patients appear to be in dynamic equilibrium. We will displace this equilibrium away from the brain by generating peptide-specific antibodies in a transgenic mouse model of Alzheimer's disease. Restricted to the peripheral circulation, these antibodies will sequester beta-amyloid peptide in the blood and by doing so gradually deplete intercommunicating peptide levels in the brain. Decreased concentrations of beta-amyloid in the brain should reduce the size and number of brain plaques or delay their appearance. The study would establish a causal relationship between amyloid deposits and memory impairment in these transgenic mice. Moreover, by virtue of their ability to perturb the soluble beta-amyloid equilibrium, our expressly designed beta-amyloid antigens and antibodies would form a basis for the immunotherapy of Alzheimer's disease.Proposed Commercial Application:Not avaliable

Thesaurus Terms:
Alzheimer's disease, immunotherapy, method development, monoclonal antibody, nonhuman therapy evaluation active immunization, neuritic plaque, passive immunization laboratory mouse, transgenic animal

The beta-amyloid peptide and the cerebral plaques that it forms are likely either the direct or indirect cause of Alzheimer's disease. This peptide is produced in both the brain and peripheral tissues by cleavage from a common cell-surface precursor protein. Soluble beta-amyloid exists free in the blood and cerebrospinal fluid while "insoluble" aggregates are deposited in the brain as amyloid plaques. The soluble and insoluble forms of beta-amyloid present within Alzheimer's patients appear to be in dynamic equilibrium. In the Phase I proposal we described how to displace this equilibrium away from the brain by generating peptide-specific antibodies in a transgenic mouse model of Alzheimer's disease. Recent studies have shown that, as we predicted, this beta-amyloid vaccine approach can prevent plaque formation in young mice and dissipate preestablished plaques in older mice. Those preclinical experiments used complete Freund's adjuvant to help elicit an immune response but such preparations are not approved for use in humans. Therefore Phase II will focus on producing and testing in animals several alternative adjuvant and antigen formulations which are compatible with clinical standards. Our expressly designed beta-amyloid antigens and adjuvants would form a basis for the immunotherapy of Alzheimer's disease using highly specific beta-amyloid vaccines. PROPOSED COMMERCIAL APPLICATIONS: The high-potency, human-compatible vaccines produced in this Phase II project have tremendous potential for use in either treating or preventing Alzheimer's disease. If successful the vaccine approach could help the large number of patients who are already suffering from the disease. It might also be used to prevent or delay the onset of disease in those who are at high risk.