AAV-delivered hepato-adrenal cooperativity in steroidogenesis: implications for gene therapy for congenital adrenal hyperplasia

IF 4.6 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-12 DOI:10.1016/j.omtm.2024.101232
Lara E. Graves, Eva B. van Dijk, Erhua Zhu, Sundar Koyyalamudi, Tiffany Wotton, Dinah Sung, Shubha Srinivasan, Samantha L. Ginn, Ian E. Alexander
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Abstract

Despite the availability of life-saving corticosteroids for 70 years, treatment for adrenal insufficiency is not able to recapitulate physiological diurnal cortisol secretion and results in numerous complications. Gene therapy is an attractive possibility for monogenic adrenocortical disorders such as congenital adrenal hyperplasia, however, requires further development of gene transfer/editing technologies and knowledge of the target progenitor cell populations. Vectors based on adeno-associated virus are the leading system for direct gene delivery but have limitations in targeting replicating cell populations such as in the adrenal cortex. One strategy to overcome this technological limitation is to deliver the relevant adrenocortical gene to a currently targetable organ outside of the adrenal cortex. To explore this possibility, we developed a vector encoding human 21-hydroxylase and directed expression to the liver in a mouse model of congenital adrenal hyperplasia. This extra-adrenal expression resulted in reconstitution of the steroidogenic pathway. Aldosterone and renin levels normalised, and corticosterone levels improved sufficiently to reduce adrenal hyperplasia. This strategy could provide an alternative treatment option for monogenic adrenal disorders, particularly for mineralocorticoid defects. These findings also demonstrate, when targeting the adrenal gland, that inadvertent liver transduction should be precluded as it may confound data interpretation.
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类固醇生成过程中的肝-肾协同作用:先天性肾上腺皮质增生症基因疗法的意义
尽管拯救生命的皮质类固醇已问世 70 年,但肾上腺功能不全的治疗无法再现皮质醇的昼夜生理分泌,并导致许多并发症。基因疗法是治疗单基因肾上腺皮质疾病(如先天性肾上腺皮质增生症)的一种有吸引力的方法,但需要进一步开发基因转移/编辑技术,并了解目标祖细胞群。基于腺相关病毒的载体是直接传递基因的主要系统,但在靶向复制细胞群(如肾上腺皮质)方面存在局限性。克服这一技术限制的策略之一是将相关肾上腺皮质基因传递到肾上腺皮质以外的可靶向器官。为了探索这种可能性,我们开发了一种编码人类 21- 羟化酶的载体,并在先天性肾上腺增生症小鼠模型中将其定向表达到肝脏。这种肾上腺外表达导致了类固醇生成途径的重建。醛固酮和肾素水平恢复正常,皮质酮水平得到改善,足以减少肾上腺增生。这种策略可为单基因肾上腺疾病,尤其是矿质皮质激素缺陷提供另一种治疗选择。这些研究结果还表明,在以肾上腺为靶点时,应避免无意中进行肝脏转导,因为这可能会混淆数据解读。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Therapy-Methods & Clinical Development
Molecular Therapy-Methods & Clinical Development Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.90
自引率
4.30%
发文量
163
审稿时长
12 weeks
期刊介绍: The aim of Molecular Therapy—Methods & Clinical Development is to build upon the success of Molecular Therapy in publishing important peer-reviewed methods and procedures, as well as translational advances in the broad array of fields under the molecular therapy umbrella. Topics of particular interest within the journal''s scope include: Gene vector engineering and production, Methods for targeted genome editing and engineering, Methods and technology development for cell reprogramming and directed differentiation of pluripotent cells, Methods for gene and cell vector delivery, Development of biomaterials and nanoparticles for applications in gene and cell therapy and regenerative medicine, Analysis of gene and cell vector biodistribution and tracking, Pharmacology/toxicology studies of new and next-generation vectors, Methods for cell isolation, engineering, culture, expansion, and transplantation, Cell processing, storage, and banking for therapeutic application, Preclinical and QC/QA assay development, Translational and clinical scale-up and Good Manufacturing procedures and process development, Clinical protocol development, Computational and bioinformatic methods for analysis, modeling, or visualization of biological data, Negotiating the regulatory approval process and obtaining such approval for clinical trials.
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