Amyloid P peptide (AD) immunization has emerged as a novel therapeutic strategy for the treatment or prevention of Alzheimer's disease (AD). In mice, the efficacy of this approach appears to be dependent on the ability to achieve a high level of anti-Ap antibody (Ab) in response to immunization with fibrillar AD or to deliver a large quantity of certain anti-AD Abs by passive immunization. In humans, there are concerns that the potential efficacy of AD immunization may be compromised due to a blunted or absent immune response to AD. One way to overcome this would be to develop humanized anti-Ap antibodies for passive immunization, however, production of large amounts of recombinant humanized antibodies is not trivial and only a small fraction of candidate therapeutic antibodies have been developed for large scale testing in humans. As an alternative approach we propose to explore recombinant adenoviral (Ad) vectors (AdVs) for in vivo production of anti-AD antibodies, and then to test these in an APP transgenic mouse model in which AD vaccination has been shown to have efficacy. In addition, we will evaluate the effects of peripheral versus CNS expression of the anti-Ap antibodies in two ways. We will compare direct injection of the recombinant anti-AD AdV into the brain versus peripheral administration and also attempt to develop AdVs tropic for the CNS that can be administered systemically but target expression to the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG021875-01
Application #
6548845
Study Section
Special Emphasis Panel (ZNS1-SRB-S (01))
Program Officer
Snyder, D Stephen
Project Start
2002-09-01
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$243,919
Indirect Cost
Name
Mayo Clinic, Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Levites, Yona; Jansen, Karen; Smithson, Lisa A et al. (2006) Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid beta, amyloid beta40, and amyloid beta42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice. J Neurosci 26:11923-8
Breidenbach, Martina; Rein, Daniel T; Schondorf, Thomas et al. (2006) A new targeting approach for breast cancer gene therapy using the heparanase promoter. Cancer Lett 240:114-22
Breidenbach, M; Rein, D T; Everts, M et al. (2005) Mesothelin-mediated targeting of adenoviral vectors for ovarian cancer gene therapy. Gene Ther 12:187-93
Wu, Hongju; Han, Tie; Belousova, Natalya et al. (2005) Identification of sites in adenovirus hexon for foreign peptide incorporation. J Virol 79:3382-90
Wang, Minghui; Hemminki, Akseli; Siegal, Gene P et al. (2005) Adenoviruses with an RGD-4C modification of the fiber knob elicit a neutralizing antibody response but continue to allow enhanced gene delivery. Gynecol Oncol 96:341-8
Everts, M; Kim-Park, S-A; Preuss, M A et al. (2005) Selective induction of tumor-associated antigens in murine pulmonary vasculature using double-targeted adenoviral vectors. Gene Ther 12:1042-8
Everts, Maaike; Curiel, David T (2004) Transductional targeting of adenoviral cancer gene therapy. Curr Gene Ther 4:337-46
Pereboev, Alexander V; Nagle, Jill M; Shakhmatov, Mikhail A et al. (2004) Enhanced gene transfer to mouse dendritic cells using adenoviral vectors coated with a novel adapter molecule. Mol Ther 9:712-20
Haviv, Yosef S; van Houdt, Winan J; Lu, Baogen et al. (2004) Transcriptional targeting in renal cancer cell lines via the human CXCR4 promoter. Mol Cancer Ther 3:687-91
Rein, Daniel T; Breidenbach, Martina; Wu, Hongju et al. (2004) Gene transfer to cervical cancer with fiber-modified adenoviruses. Int J Cancer 111:698-704

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