Protein overexpression by adeno-associated virus-based gene therapy products in cardiomyocytes induces endoplasmic reticulum stress and myocardial degeneration in mice.

Autor:	Yasuno K; Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan., Watanabe R; Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan., Ishida R; Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan., Okado K; Department of Translational Research, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan., Kondo H; Discovery Research Laboratories IV, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan., Iguchi T; Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan., Imaoka M; Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan., Tsuchiya Y; Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
Jazyk:	angličtina
Zdroj:	Journal of toxicologic pathology [J Toxicol Pathol] 2024 Oct; Vol. 37 (4), pp. 139-149. Date of Electronic Publication: 2024 Jun 07.
DOI:	10.1293/tox.2024-0011
Abstrakt:	Gene therapy (GT) products created using adeno-associated virus (AAV) vectors tend to exhibit toxicity via immune reactions, but other mechanisms of toxicity remain incompletely understood. We examined the cardiotoxicity of an overexpressed transgenic protein. Male C57BL/6J mice were treated with a single intravenous dose of product X, an AAV-based GT product, at 2.6 × 10 13 vg/kg. Necropsies were performed at 24 h, 7 days, and 14 days after dosing. Pathological examination and gene expression analysis were performed on the heart. Histopathologically, hypertrophy and vacuolar degeneration of cardiomyocytes and fibrosis were observed 14 days after dosing. Immunohistochemistry for endoplasmic reticulum (ER) stress-related proteins revealed increased positive reactions for glucose-regulated protein 78 and C/EBPR homologous protein in cardiomyocytes 7 days after dosing, without histopathological abnormalities. Fourteen days after dosing, some cardiomyocytes showed positivity for PKR-like endoplasmic reticulum kinase and activating transcription factor 4 expression. Ultrastructurally, increases in the ER and cytosol were observed in cardiomyocytes 7 days after dosing, along with an increase in the number of Golgi apparatus compartments 14 days after dosing. The tissue concentration of the transgene product protein increased 7 days after dosing. Gene expression analysis showed upregulation of ER stress-related genes 7 days after dosing, suggesting activation of the PKR-like ER kinase pathway of the unfolded protein reaction (UPR). Thus, the cardiotoxicity induced by product X was considered to involve cell damage caused by the overexpression of the product protein accompanied by UPR. Marked UPR activation may also cause toxicity of AAV-based GT products. Competing Interests: Kyohei Yasuno, Ryo Watanabe, Rumiko Ishida, Hirofumi Kondo, Masako Imaoka, and Yoshimi Tsuchiya are employees of Daiichi Sankyo Co., Ltd. Keiko Okado is an employee of Daiichi Sankyo RD Novare Co., Ltd. (©2024 The Japanese Society of Toxicologic Pathology.)
Databáze:	MEDLINE
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