Reversing Pathology in an Aggravated Fabry Mouse Model Using Low-Dose Engineered Human Alpha-Galactosidase A AAV Gene Therapy
<b>Background/Objectives</b>: Fabry disease is an X-linked disorder caused by lysosomal accumulation of glycosphingolipids due to the deficiency of α-Galactosidase (α-GAL), which leads to pathology in multiple organ systems. The standard of care is enzyme replacement therapy (ERT) with r...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-02-01
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| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/13/3/577 |
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| Summary: | <b>Background/Objectives</b>: Fabry disease is an X-linked disorder caused by lysosomal accumulation of glycosphingolipids due to the deficiency of α-Galactosidase (α-GAL), which leads to pathology in multiple organ systems. The standard of care is enzyme replacement therapy (ERT) with recombinant native α-GAL protein. Shortcomings of the native α-GAL include low stability, a short circulating half-life, and inadequate uptake by affected tissues that limits the efficacy of ERT and could potentially reduce AAV gene therapy (GT) benefits. Cross-correction by secreted α-GAL is essential for liver-targeted as well as ubiquitous AAV GT due to poor transduction and/or short half-life of some of the significantly affected cell types. <b>Methods</b>: To overcome potential limitations of AAV GT delivering native α-GAL, we used an engineered <i>GLA</i> transgene product to improve enzyme stability and reduce predicted immunogenicity. <b>Results</b>: The stabilized α-GAL variant, Eng-C, had an extended circulatory half-life, allowing for enhanced distribution and efficient uptake by target organs. AAV gene therapy with Eng-C demonstrated significantly greater substrate reduction in the severe Fabry G3Stg/<i>Gla</i>KO mouse model across all affected tissues. Efficacy of the Eng-C AVV GT was equal to or greater than the efficacy of the higher doses of the AAV GT with native α-GAL. Furthermore, this study is the first to demonstrate that the pre-existing pathology in some tissues in G3Stg/<i>Gla</i>KO mice can be reversed with efficient treatment. <b>Conclusions</b>: Our findings demonstrate that an AAV-based gene therapy expressing an engineered α-GAL with improved stability and lower immunogenicity could be effective at lower doses than other AAV GTs, potentially offering lower safety risks typically associated with high AAV vector doses. |
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| ISSN: | 2227-9059 |