Efficacy of oligodendrocyte precursor cells as delivery vehicles for single-chain variable fragment to misfolded SOD1 in ALS rat model

Sumio Minamiyama; Madoka Sakai; Yuko Yamaguchi; Makiko Kusui; Hideki Wada; Ryota Hikiami; Yoshitaka Tamaki; Megumi Asada-Utsugi; Akemi Shodai; Akiko Makino; Noriko Fujiwara; Takashi Ayaki; Takakuni Maki; Hitoshi Warita; Masashi Aoki; Keizo Tomonaga; Ryosuke Takahashi; Makoto Urushitani

doi:10.1016/j.omtm.2023.01.008

Efficacy of oligodendrocyte precursor cells as delivery vehicles for single-chain variable fragment to misfolded SOD1 in ALS rat model

Mol Ther Methods Clin Dev. 2023 Feb 4:28:312-329. doi: 10.1016/j.omtm.2023.01.008. eCollection 2023 Mar 9.

Authors

Sumio Minamiyama^{1

2}, Madoka Sakai^{3

4}, Yuko Yamaguchi², Makiko Kusui¹, Hideki Wada¹, Ryota Hikiami^{1

2}, Yoshitaka Tamaki¹, Megumi Asada-Utsugi¹, Akemi Shodai¹, Akiko Makino^{3

4}, Noriko Fujiwara⁵, Takashi Ayaki², Takakuni Maki², Hitoshi Warita⁶, Masashi Aoki⁶, Keizo Tomonaga^{3

4

7}, Ryosuke Takahashi², Makoto Urushitani¹

Affiliations

¹ Department of Neurology, Shiga University of Medical Science, Otsu, Shiga 5202192, Japan.
² Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan.
³ Laboratory of RNA Viruses, Department of Virus Research, Institute for Frontier Life and Medical Sciences (InFRONT), Kyoto University, Kyoto 6068507, Japan.
⁴ Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Kyoto 6068507, Japan.
⁵ Department of Biochemistry, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo 6638501, Japan.
⁶ Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 9808574, Japan.
⁷ Department of Molecular Virology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan.

Abstract

Superoxide dismutase1 (SOD 1) mutation is a leading cause of familial amyotrophic lateral sclerosis (ALS). Growing evidence suggests that antibody therapy against misfolded SOD1 protein can be therapeutic. However, the therapeutic effects are limited, partly because of the delivery system. Therefore, we investigated the efficacy of oligodendrocyte precursor cells (OPCs) as a drug delivery vehicle of single-chain variable fragments (scFv). Using a Borna disease virus vector that is pharmacologically removable and episomally replicable in the recipient cells, we successfully transformed wild-type OPCs to secrete scFv of a novel monoclonal antibody (D3-1), specific for misfolded SOD1. Single intrathecal injection of OPCs scFvD3-1, but not OPCs alone, significantly delayed disease onset and prolonged the lifespan of ALS rat models expressing SOD1 ^H46R . The effect of OPC scFvD3-1 surpassed that of a 1 month intrathecal infusion of full-length D3-1 antibody alone. scFv-secreting OPCs suppressed neuronal loss and gliosis, reduced levels of misfolded SOD1 in the spinal cord, and suppressed the transcription of inflammatory genes, including Olr1, an oxidized low-density lipoprotein receptor 1. The use of OPCs as a delivery vehicle for therapeutic antibodies is a new option for ALS in which misfolded protein and oligodendrocyte dysfunction are implicated in the pathogenesis.

Keywords: amyotrophic lateral sclerosis (ALS); oligodendrocyte precursor cells; single-chain variable fragments (scFv); superoxide dismutase 1 (SOD1); transplantation; viral vector.