Development of a rabbit model for adrenoleukodystrophy: A pilot study on gene therapy using rAAV9
X-linked adrenoleukodystrophy (X-ALD) is a common peroxisomal disorder caused by mutations in the <i>ABCD1</i> gene, leading to the accumulation of very long-chain fatty acids (VLCFAs). This progressive neurodegenerative disease manifests in three primary forms: childhood-acquired cerebral demyelination (CALD), adult myelopathy (AMN), and primary adrenal cortical insufficiency. Bone marrow transplantation effectively halts disease progression only in the early stages of CALD. A thorough investigation of the pathophysiology of X-ALD has been hampered by the lack of a reliable animal model. Valid animal models of X-ALD are urgently needed. To address this, we used CRISPR-Cas9 technology to knock out the <i>ABCD1</i> gene and established a novel rabbit model of X-ALD. The mutants exhibited elevated serum levels of hexacosanoic acid (C26:0), lignoceric acid (C24:0), and an increased C26:0/C22:0 ratio, as well as significant white matter demyelination in the brain and spinal cord. We also investigated rAAV9-based gene therapy in this model and found a significant reduction in VLCFAs. This study introduces CRISPR-Cas9-mediated <i>ABCD1</i> gene knockout rabbits as a novel animal model. It comprehensively evaluates the short-term outcomes and safety of rAAV-based gene therapy for X-ALD, providing a promising approach to explore the molecular and pharmacological mechanisms of the disease.
Authors
- Zhanjun Li (ORCID: https://orcid.org/0000-0001-6914-8589)
- Meng Kou
- Zhejin Li (ORCID: https://orcid.org/0000-0002-1609-7252)
- Jie Luo (ORCID: https://orcid.org/0000-0002-4931-7469)
- Zhijian Lin (ORCID: https://orcid.org/0000-0002-7609-1143)
- Xia Xu (ORCID: https://orcid.org/0000-0003-1304-5171)
- Liangxue Lai
- Fuyu Duan (ORCID: https://orcid.org/0000-0001-5628-5226)
- Qizhou Lian (ORCID: https://orcid.org/0000-0001-8189-7160)
- Shaoxiang Chen (ORCID: https://orcid.org/0000-0002-9262-7657)
- Hongsheng Liu (ORCID: https://orcid.org/0000-0003-4188-9638)
- Li Chen (ORCID: https://orcid.org/0000-0002-8120-5758)
- Xiaoya Zhou (ORCID: https://orcid.org/0000-0002-6946-7122)
- Ping Yuan (ORCID: https://orcid.org/0000-0001-5458-3297)
- Ziyue Li (ORCID: https://orcid.org/0000-0002-5040-6696)
- Jieying Wu (ORCID: https://orcid.org/0000-0002-6277-3960)
- Tingting Sui (ORCID: https://orcid.org/0000-0002-8865-0862)
- Hao Chen (ORCID: https://orcid.org/0009-0000-6276-6405)
- Xiaoxian Zhang
- Chui-Yan Ma
- Liyan Guo
- Liang Zeng (ORCID: https://orcid.org/0009-0007-4329-6031)
Institutions
- Sun Yat-sen University (CN)
- Jilin University (CN)
- Chinese Academy of Sciences (CN)
- Guangzhou Institutes of Biomedicine and Health (CN)
- Sixth Affiliated Hospital of Sun Yat-sen University (CN)
- Cell Technology (China) (HK)
- Peking University Shenzhen Hospital (CN)
- University of Hong Kong - Shenzhen Hospital (CN)
- Guangdong Academy of Medical Sciences (CN)
- Shenzhen Institutes of Advanced Technology (CN)
- Guangdong Provincial People's Hospital (CN)
- Southern Medical University (CN)
- University of Hong Kong (HK)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Molecular Therapy — Nucleic Acids
- Published
- 2025-02-03
- DOI
- https://doi.org/10.1016/j.omtn.2025.102469
- Citations
- 2
- Primary Topic
- Peroxisome Proliferator-Activated Receptors
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Guangzhou Medical University
- National Key Research and Development Program of China
- National Key Research and Development Program of China Stem Cell and Translational Research
- Shenzhen Science and Technology Innovation Program