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Updated: Sep 13, 2025

Isolation of Next-Generation Gene Therapy Vectors through Engineering, Barcoding, and Screening of Adeno-Associated Virus AAV Capsid Variants

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AAV8-based gene replacement therapy for hereditary spastic paraplegia type 5.

Linus Wiora^1,2,3,4, 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.

Keywords:

AAV CYP7B1 SPG5 cholesterol gene therapy hereditary spastic paraplegia neurodegeneration oxysterols

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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.