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AAV8-based gene replacement therapy for hereditary spastic paraplegia type 5
Linus Wiora1,2,3,4, Qinggong Yuan5, Sebastian Hook5
1German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
Molecular Therapy. Methods & Clinical Development
|July 31, 2025
Summary
Gene therapy targeting the liver normalized cholesterol metabolism in a mouse model of Hereditary Spastic Paraplegia type 5 (SPG5). However, brain oxysterol levels remained partially corrected, indicating a need for CNS-targeted approaches.
Area of Science:
- Neurogenetics
- Metabolic Disorders
- Gene Therapy
Background:
- Hereditary Spastic Paraplegia type 5 (SPG5) is an autosomal recessive neurological disorder.
- Mutations in the CYP7B1 gene disrupt cholesterol metabolism, leading to neurotoxic oxysterol accumulation.
- Elevated 25- and 27-hydroxycholesterol contribute to SPG5 pathogenesis, causing gait disturbance and reduced quality of life.
Purpose of the Study:
- To develop and evaluate a liver-targeted gene therapy for SPG5 using a Cyp7b1-/- mouse model.
- To assess the efficacy of correcting oxysterol imbalance and its impact on SPG5 phenotypes.
Main Methods:
- Development of an AAV8-TTR-hCYP7B1 vector for liver-specific CYP7B1 gene delivery.
- Intravenous administration of the gene therapy vector to the mouse model.
- Monitoring of oxysterol levels in blood, liver, and brain post-treatment.
Main Results:
- Rapid normalization of oxysterol levels in blood and liver at low doses (1E10) without toxicity.
- Partial correction of brain oxysterol levels, particularly 27-hydroxycholesterol, six weeks post-treatment.
- Demonstrated effectiveness of liver-targeted gene therapy in restoring peripheral cholesterol metabolism.
Conclusions:
- Liver-targeted gene therapy shows promise for SPG5 by normalizing peripheral metabolism.
- A comprehensive therapeutic strategy for SPG5 must address central nervous system oxysterol accumulation.
- Novel gene therapeutic approaches targeting the CNS are required for effective SPG5 treatment.
