Carisi Maria Carla, Shamber Claire, Bishop Martha, Sangster Madison, Chandrachud Uma, Meyerink Brandon, Pilaz Louis Jean, Grishchuk Yulia
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, USA.
Pediatrics and Rare Diseases Group, Sanford Research Institute, University of South Dakota, Sioux Falls, South Dakota, USA.
Hum Gene Ther. 2025 Mar;36(5-6):637-652. doi: 10.1089/hum.2024.224. Epub 2025 Feb 20.
Beta-propeller protein-associated neurodegeneration (BPAN) is an ultra-rare, X-linked dominant, neurodevelopmental, and neurodegenerative disease caused by loss-of-function mutations in the gene. It manifests in neurodevelopmental delay and seizures followed by secondary neurological decline with dystonia/parkinsonism and dementia in adolescence and early adulthood and is characterized by progressive accumulation of iron in the basal ganglia. encodes β-propeller-shaped scaffold protein, or WD repeat domain phosphoinositide-interacting protein 4 (WIPI4), which plays an important role in autophagosome formation. While the mechanisms of how WIPI4 loss of function results in neurological decline and brain pathology have not yet been established, findings of lower autophagic activity provide a direct link between impaired autophagy and neurological disease in BPAN. Here we performed phenotypical characterization of a novel mouse model of BPAN, Wdr45_ex9+1g>a mouse. We identified hyperactive behavior and reduction of autophagy markers in brain tissue in Wdr45_ex9+1g>a hemizygous males as early as at 2 months of age. Given the early onset and spectrum of neurological symptoms such as hyper-arousal and attention deficits in human patients, this model presents a disease-relevant phenotype and can be used in preclinical studies. We used this mouse model for a proof-of-concept study to evaluate whether adeno-associated virus (AAV)-mediated central nervous system (CNS)-targeted gene transfer of can provide therapeutic benefit and be considered a therapeutic paradigm for BPAN. We observed successful expression of human transcripts and WIPI4 protein in the brain tissue, rescue of hyperactive behavior, and correction of autophagy markers. These data demonstrate that gene transfer can be a promising therapeutic strategy for BPAN.
β-螺旋桨蛋白相关神经退行性疾病（BPAN）是一种极其罕见的、X连锁显性遗传的神经发育和神经退行性疾病，由该基因的功能丧失突变引起。它表现为神经发育迟缓与癫痫发作，随后在青少年期和成年早期出现继发性神经功能衰退，伴有肌张力障碍/帕金森综合征和痴呆，其特征是基底神经节中铁的逐渐积累。该基因编码β-螺旋桨形状的支架蛋白，即WD重复结构域磷酸肌醇相互作用蛋白4（WIPI4），它在自噬体形成中起重要作用。虽然WIPI4功能丧失导致神经功能衰退和脑部病变的机制尚未明确，但自噬活性降低的研究结果为BPAN中自噬受损与神经疾病之间提供了直接联系。在此，我们对一种新型BPAN小鼠模型Wdr45_ex9+1g>a小鼠进行了表型特征分析。我们发现，早在2月龄时，Wdr45_ex9+1g>a半合子雄性小鼠的脑组织中就出现了多动行为以及自噬标志物减少的情况。鉴于人类患者中存在诸如过度兴奋和注意力缺陷等神经症状的早发和症状谱，该模型呈现出与疾病相关的表型，可用于临床前研究。我们使用该小鼠模型进行了一项概念验证研究，以评估腺相关病毒（AAV）介导的中枢神经系统（CNS）靶向的该基因转移是否能提供治疗益处，并被视为BPAN的一种治疗模式。我们观察到脑组织中人类该转录本和WIPI4蛋白的成功表达、多动行为的改善以及自噬标志物的纠正。这些数据表明，该基因转移可能是BPAN一种有前景的治疗策略。
