An Oral Aβ Vaccine Using a Recombinant Adeno-Associated Virus Vector in Aged Monkeys: Reduction in Plaque Amyloid and Increase in Aβ Oligomers

Article type: Research Article

Authors: Hara, Hideo^{a; b} | Ono, Fumiko^{c; d} | Nakamura, Shinichiro^{c; e} | Matsumoto, Shin-ei^{a; f} | Jin, Haifeng^f | Hattori, Nobutaka^f | Tabira, Takeshi^{a; f}

Affiliations: [a] National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Morioka, Obu, Aichi, Japan | [b] Division of Neurology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan | [c] The Corporation for Production and Research of Laboratory Primates, Tsukuba, Ibaraki, Japan | [d] Faculty of Risk and Crisis Management, Chiba Institute of Science, Shiomi, Choshi, Chiba, Japan | [e] Shiga University of Medical Science, Research Center for Animal Life Science, Seta-Tsukinowa, Otsu, Shiga, Japan | [f] Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan

Correspondence: [*] Correspondence to: Takeshi Tabira, Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Medicine, Juntendo University, 2-11-5-3F Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel./Fax: +81 3 6801 8332; E-mail: [email protected].

Abstract: With the objective to improve the amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an oral vaccine with recombinant adeno-associated virus vector carrying a signal sequence and Aβ1-43 cDNA (rAAV/Aβ) in old non-human primates, 12 African green and 10 cynomolgus monkeys. The enteric-dissolving coated capsules containing rAAV/Aβ were orally administered once or twice, then monkeys’ conditions were carefully observed with complete blood count and laboratory examinations of the sera. General conditions, food intake, water intake, stool conditions, body weight changes, and menstruation cycles were not significantly altered, and laboratory tests and pathological examinations of the systemic organs were unremarkable. Pathological examinations of the brain showed significant reduction of the amyloid plaque burden and intracellular Aβ without inflammatory or hemorrhagic changes in the brain. However, soluble Aβ and some Aβ oligomers were increased in rAAV-treated monkey brains without changes of the neuronal density and vascular amyloidosis. Thus, this vaccine seems to be safe in general, but we must be cautious about the increase of Aβ oligomers after vaccination. This vaccine may be recommended at a very early stage of Alzheimer’s disease when little amyloid is deposited.

Keywords: Adeno-associated virus vector, Alzheimer’s disease, amyloid-beta, Aβ oligomer, primate, vaccine

DOI: 10.3233/JAD-160514

Journal: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1047-1059, 2016