mRNA as a Novel Treatment Strategy for Hereditary Spastic Paraplegia Type 5

Stefan Hauser; Marion Poenisch; Yvonne Schelling; Philip Höflinger; Stefanie Schuster; Axel Teegler; Rabea Betten; Jan-Åke Gustafsson; Jeannette Hübener-Schmid; Thomas Schlake; Frédéric Chevessier-Tünnesen; Nigel Horscroft; Ingemar Björkhem; Ludger Schöls

doi:10.1016/j.omtm.2019.10.011

mRNA as a Novel Treatment Strategy for Hereditary Spastic Paraplegia Type 5

Mol Ther Methods Clin Dev. 2019 Oct 31:15:359-370. doi: 10.1016/j.omtm.2019.10.011. eCollection 2019 Dec 13.

Authors

Stefan Hauser^{1

2}, Marion Poenisch³, Yvonne Schelling^{1

2}, Philip Höflinger^{1

2

4}, Stefanie Schuster^{1

2

4}, Axel Teegler³, Rabea Betten³, Jan-Åke Gustafsson^{5

6}, Jeannette Hübener-Schmid⁷, Thomas Schlake³, Frédéric Chevessier-Tünnesen³, Nigel Horscroft³, Ingemar Björkhem⁸, Ludger Schöls^{1

2}

Affiliations

¹ German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
² Department of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
³ CureVac AG, Paul-Ehrlich-Strasse 15, 72076 Tübingen, Germany.
⁴ Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, 72076 Tübingen, Germany.
⁵ Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, 141 83 Huddinge, Sweden.
⁶ Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204, USA.
⁷ Institute of Medical Genetics and Applied Genomics and Center of Rare Diseases, University of Tübingen, 72076 Tübingen, Germany.
⁸ Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.

Abstract

Hereditary spastic paraplegia type 5 is a neurodegenerative disease caused by loss-of-function mutations in the CYP7B1 gene encoding the oxysterol 7-α-hydroxylase involved in bile acid synthesis in the liver. Lack of CYP7B1 leads to an accumulation of its oxysterol substrates, in particular 25-hydroxycholesterol and 27-hydroxycholesterol that are able to cross the blood-brain barrier and have neurotoxic properties. A potential therapeutic strategy for SPG5 is the replacement of CYP7B1 by administration of mRNA. Here, we studied the intravenous application of formulated mouse and human CYP7B1 mRNA in mice lacking the endogenous Cyp7b1 gene. A single-dose injection of either mouse or human CYP7B1 mRNA led to a pronounced degradation of oxysterols in liver and serum within 2 days of treatment. Pharmacokinetics indicate a single injection of human CYP7B1 mRNA to be effective in reducing oxysterols for at least 5 days. Repetitive applications of mRNA were safe for at least 17 days and resulted in a significant reduction of neurotoxic oxysterols not only in liver and serum but also to some extent in the brain. Our study highlights the potential to use mRNA as a novel therapy to treat patients with SPG5 disease.

Keywords: CYP7B1; Hereditary spastic paraplegia; SPG5; gene therapy; mRNA therapy.