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Journal of Virology, May 2004, p. 4999-5006, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.4999-5006.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Treatment of Transmissible Spongiform Encephalopathy by Intraventricular Drug Infusion in Animal Models

Katsumi Doh-ura,1* Kensuke Ishikawa,1,{dagger} Ikuko Murakami-Kubo,1 Kensuke Sasaki,1 Shirou Mohri,2 Richard Race,3 and Toru Iwaki1

Department of Neuropathology,1 Center of Biomedical Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan,2 Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 598403

Received 6 October 2003/ Accepted 9 January 2004

The therapeutic efficacy of direct drug infusion into the brain, the target organ of transmissible spongiform encephalopathies, was assessed in transgenic mice intracerebrally infected with 263K scrapie agent. Pentosan polysulfate (PPS) gave the most dramatic prolongation of the incubation period, and amphotericin B had intermediate effects, but antimalarial drugs such as quinacrine gave no significant prolongation. Treatment with the highest dose of PPS at an early or late stage of the infection prolonged the incubation time by 2.4 or 1.7 times that of the control mice, respectively. PPS infusion decreased not only abnormal prion protein deposition but also neurodegenerative changes and infectivity. These alterations were observed within the brain hemisphere fitted with an intraventricular infusion cannula but not within the contralateral hemisphere, even at the terminal disease stage long after the infusion had ended. Therapeutic effects of PPS were also demonstrated in mice infected with either RML agent or Fukuoka-1 agent. However, at doses higher than that providing the maximal effects, intraventricular PPS infusion caused adverse effects such as hematoma formation in the experimental animals. These findings indicate that intraventricular PPS infusion might be useful for the treatment of transmissible spongiform encephalopathies in humans, providing that the therapeutic dosage is carefully evaluated.

* Corresponding author. Present address: Department of Prion Research, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan. Phone: 81-22-717-8232. Fax: 81-22-717-8148. E-mail: doh-ura{at}mail.tains.tohoku.ac.jp.

{dagger} Present address: Department of Prion Research, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

Journal of Virology, May 2004, p. 4999-5006, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.4999-5006.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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