Bonten Erik J, Yogalingam Gouri, Hu Huimin, Gomero Elida, van de Vlekkert Diantha, d'Azzo Alessandra
Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Biochim Biophys Acta. 2013 Oct;1832(10):1784-92. doi: 10.1016/j.bbadis.2013.06.002. Epub 2013 Jun 12.
The lysosomal storage disease sialidosis is caused by a primary deficiency of the sialidase N-acetyl-α-neuraminidase-1 (NEU1). Patients with type I sialidosis develop an attenuated, non-neuropathic form of the disease also named cherry red spot myoclonus syndrome, with symptoms arising during juvenile/ adult age. NEU1 requires binding to its chaperone, protective protein/cathepsin A (PPCA), for lysosomal compartmentalization, stability and catalytic activation. We have generated a new mouse model of type I sialidosis that ubiquitously expresses a NEU1 variant carrying a V54M amino acid substitution identified in an adult patient with type I sialidosis. Mutant mice developed signs of lysosomal disease after 1year of age, predominantly in the kidney, albeit low residual NEU1 activity was detected in most organs and cell types. We demonstrate that the activity of the mutant enzyme could be effectively increased in all systemic tissues by chaperone-mediated gene therapy with a liver-tropic recombinant AAV2/8 vector expressing PPCA. This resulted in clear amelioration of the disease phenotype. These results suggest that at least some of the NEU1 mutations associated with type I sialidosis may respond to PPCA-chaperone-mediated gene therapy.
溶酶体贮积病唾液酸沉积症是由唾液酸酶N - 乙酰 - α - 神经氨酸酶 - 1（NEU1）原发性缺乏引起的。I型唾液酸沉积症患者会发展出一种症状较轻的非神经性疾病形式，也称为樱桃红斑肌阵挛综合征，症状在青少年/成年期出现。NEU1需要与它的伴侣蛋白——保护蛋白/组织蛋白酶A（PPCA）结合，以实现溶酶体区室化、稳定性和催化激活。我们构建了一种新的I型唾液酸沉积症小鼠模型，该模型普遍表达一种携带V54M氨基酸替代的NEU1变体，此变体是在一名成年I型唾液酸沉积症患者中发现的。突变小鼠在1岁后出现了溶酶体疾病的迹象，主要发生在肾脏，尽管在大多数器官和细胞类型中检测到了低残留的NEU1活性。我们证明，通过用表达PPCA的肝脏靶向重组AAV2/8载体进行伴侣介导的基因治疗，可以有效提高突变酶在所有全身组织中的活性。这导致了疾病表型的明显改善。这些结果表明，至少一些与I型唾液酸沉积症相关的NEU1突变可能对PPCA伴侣介导的基因治疗有反应。
