Nijhuis Paul J H, Romijn Maurits, Honing Roy, van Zon Giselle, Huitinga Inge, de Winter Fred, Verhaagen Joost
Laboratory of Neuroregeneration, The Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, the Netherlands.
Laboratory of Neuroimmunology, The Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, the Netherlands.
Mol Ther Methods Clin Dev. 2025 Jun 10;33(3):101504. doi: 10.1016/j.omtm.2025.101504. eCollection 2025 Sep 11.
Multiple sclerosis (MS) is a neurological disease characterized by demyelinating lesions in the CNS. This study investigated whether a minimally invasive adeno-associated virus (AAV) vector (AAV.PHP.eB) can direct transgene expression in CNS cell types relevant to MS, including astrocytes, oligodendrocytes, oligodendrocyte precursor cells (OPCs), microglia, and neurons in experimental autoimmune encephalitis, a widely used MS model. bioluminescence imaging and histological analysis following AAV.PHP.eB-mediated gene delivery in healthy mice using the ubiquitous CAG promoter and five neural promoters (MBP, Sox10, hSyn1, gfa2, and gfaABC1D) revealed long-term, robust, and cell-type-specific activity across the brain and spinal cord. AAV.PHP.eB is capable of traversing the blood-brain barrier in experimental autoimmune encephalitis (EAE) and directs sustained and cell-type-specific transgene expression for the MBP, Sox10, hSyn1, and gfaABC1D promoters. The MBP and Sox10 promoters directed transgene expression in oligodendroglia around and within inflammatory demyelinating lesions, whereas the gfaABC1D promoter directs transgene expression in gray and white matter astrocytes and hSyn1 in neurons. The neural promoters were minimally active in the periphery, with the exception of gfa2. This methodological study is a first step toward the development of minimally invasive gene therapy to promote myelin repair and/or suppress inflammation in MS.
多发性硬化症（MS）是一种以中枢神经系统（CNS）脱髓鞘病变为特征的神经疾病。本研究调查了一种微创腺相关病毒（AAV）载体（AAV.PHP.eB）是否能在与MS相关的中枢神经系统细胞类型中指导转基因表达，这些细胞类型包括星形胶质细胞、少突胶质细胞、少突胶质前体细胞（OPC）、小胶质细胞，以及在实验性自身免疫性脑脊髓炎（一种广泛使用的MS模型）中的神经元。在健康小鼠中使用普遍存在的CAG启动子和五个神经启动子（MBP、Sox10、hSyn1、gfa2和gfaABC1D）进行AAV.PHP.eB介导的基因传递后，生物发光成像和组织学分析显示，在整个脑和脊髓中具有长期、强大且细胞类型特异性的活性。AAV.PHP.eB能够穿越实验性自身免疫性脑脊髓炎（EAE）中的血脑屏障，并针对MBP、Sox10、hSyn1和gfaABC1D启动子指导持续且细胞类型特异性的转基因表达。MBP和Sox10启动子在炎性脱髓鞘病变周围和内部的少突胶质细胞中指导转基因表达，而gfaABC1D启动子在灰质和白质星形胶质细胞中指导转基因表达，hSyn1在神经元中指导转基因表达。除gfa2外，神经启动子在外周的活性极低。这项方法学研究是朝着开发微创基因疗法以促进MS中的髓鞘修复和/或抑制炎症迈出的第一步。
