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

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)359-370
Number of pages12
JournalMolecular Therapy - Methods and Clinical Development
Volume15
DOIs
StatePublished - Dec 13 2019

Keywords

  • CYP7B1
  • Hereditary spastic paraplegia
  • SPG5
  • gene therapy
  • mRNA therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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