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Published on: August 10, 2018
mRNA as a Novel Treatment Strategy for Hereditary Spastic Paraplegia Type 5
Stefan Hauser1,2, Marion Poenisch3, Yvonne Schelling1,2
1German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
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.
Insights
Messenger RNA (mRNA) therapy effectively reduces neurotoxic oxysterols in a mouse model of Hereditary Spastic Paraplegia type 5 (SPG5). This approach shows promise for treating this neurodegenerative disease.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Hereditary Spastic Paraplegia type 5 (SPG5) is a neurodegenerative disorder caused by mutations in the CYP7B1 gene.
- CYP7B1 deficiency leads to accumulation of neurotoxic oxysterols, such as 25-hydroxycholesterol and 27-hydroxycholesterol, which can cross the blood-brain barrier.
- Current therapeutic strategies for SPG5 are limited.
Purpose of the Study:
- To investigate the potential of messenger RNA (mRNA) therapy for SPG5 by studying the intravenous administration of CYP7B1 mRNA.
- To assess the efficacy and safety of CYP7B1 mRNA in reducing neurotoxic oxysterols in a mouse model lacking the endogenous Cyp7b1 gene.
Main Methods:
- Intravenous injection of formulated mouse and human CYP7B1 mRNA into mice with a genetic deficiency in Cyp7b1.
- Measurement of oxysterol levels in liver, serum, and brain following single and repetitive mRNA administrations.
- Pharmacokinetic analysis to determine the duration of mRNA efficacy.
Main Results:
- A single dose of CYP7B1 mRNA significantly reduced oxysterols in the liver and serum within 2 days.
- Human CYP7B1 mRNA demonstrated sustained oxysterol reduction for at least 5 days after a single injection.
- Repetitive mRNA treatments were safe for up to 17 days and reduced neurotoxic oxysterols in liver, serum, and to some extent, the brain.
Conclusions:
- Intravenous administration of CYP7B1 mRNA is a viable strategy for reducing neurotoxic oxysterols in SPG5.
- mRNA therapy demonstrates potential as a novel therapeutic approach for patients with Hereditary Spastic Paraplegia type 5.
- Further research is warranted to explore the clinical application of mRNA-based therapies for SPG5.
