Promising results in mouse studies
Messenger RNA, a precursor of DNA, has shown potential as a treatment for SPG5 type HSP in this study of SPG5 mice. Positive effects were noted within two days of treatment; a single injection produced results for at least five days and repetitive treatment was shown safe for at least 17 days with significant reductions in toxic lipids in the liver, the blood and also to some extent in the brain.
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.
SOURCE: Mol Ther Methods Clin Dev. 2019 Oct 31;15:359-370. doi: 10.1016/j.omtm.2019.10.011. eCollection 2019 Dec 13. PMID: 31828178 © 2019 The Author(s).
mRNA as a Novel Treatment Strategy for Hereditary Spastic Paraplegia Type 5.
Hauser S1,2, Poenisch M3, Schelling Y1,2, Höflinger P1,2,4, Schuster S1,2,4, Teegler A3, Betten R3, Gustafsson JÅ5,6, Hübener-Schmid J7, Schlake T3, Chevessier-Tünnesen F3, Horscroft N3, Björkhem I8, Schöls L1,2.
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.