Retinal Gene Therapy for Usher Syndrome: Current Developments, Challenges, and Perspectives.
Retinal Gene Therapy for Usher Syndrome: Current Developments, Challenges, and Perspectives.
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DOI：
10.1097/iio.0000000000000378
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发表时间：
2021-10-01
影响因子：
--
通讯作者：
Saperstein DA
中科院分区：
文献类型：
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作者：
Dinculescu A;Link BA;Saperstein DA
Usher综合征（USH）是一组遗传异质性常染色体隐性遗传病，以视觉和感音神经性听力损失合并为特征，在某些情况下还包括前庭功能障碍。它主要影响视网膜中的感光细胞和耳蜗中的听觉毛细胞。所有病例的视力丧失都是进行性的，表现为色素性视网膜炎（RP），其特征是感光细胞逐渐退化。周围视杆细胞功能首先丧失，导致夜盲症和视野狭窄，其次是视锥细胞死亡和严重的视力障碍。目前还没有药物或生物疗法被证明能有效治疗USH综合征。人工耳蜗植入术绕过受损毛细胞，直接刺激初级听觉神经元，是缓解患者听力障碍的有效途径。然而，视网膜中感光神经元的进行性丧失尚无补救措施，因此，开发预防USH综合征失明的治疗策略是一个关键的未满足需求。生成忠实地模拟人类USH疾病的动物模型、基因治疗干预的时机、正确靶细胞的识别和患者的选择是成功实现这一目标的关键因素。USH综合征是以苏格兰眼科医生查尔斯·霍华德·亚瑟的名字命名的，他在1914年描述了69名患有这种疾病的患者。5与医学上常见的情况一样，这种疾病在更早的时候（1858年）由von Gräfe在患有失明和耳聋的兄弟身上首次描述，7 3年后由他的学生Liebreich在更大的患者群体中进一步描述。从发现到最近，USH综合征及其亚群是根据临床特征来划分的。现在这种疾病是通过症状识别和基因分型来分类的。迄今为止，至少有10种致病基因与USH综合征相关，在以前的综述中进行了总结。1,2,9总的来说，根据其临床症状的多样性，特别是感音神经性听力障碍的发病和严重程度以及前庭功能障碍的存在，USH综合征可分为3个临床亚型。I型疾病与严重至深度语前听力损失、前庭异常和青春期前RP症状发作有关。10,11 USH1源于MYO7A （USH1B）、HARMONIN （USH1C）、CDH23 （USH1D）、PCDH15 （USH1F）、SANS （USH1G）和CIB2 （USH1J）的突变。II型疾病患者表现为中度至重度先天性听力损失，无前庭功能障碍，占所有USH病例的50%。他们的RP症状通常在第二个十年开始。12 USH2是由USH2A （USH2A）、ADGRV1 （USH2C）和WHRN （USH2D）突变引起的。CLRN1 （USH3A）基因突变引起的III型疾病患者有语后进行性听力损失、变异性前庭功能障碍和变异性RP，并在生命的第四个十年迅速发展为法定失明。HARS基因（组氨酸- trna合成酶）的突变与超罕见的USH3B有关。18,19在非典型USH病例中还发现了其他基因，包括：编码中心体相关蛋白CEP家族成员的CEP250和CEP78；ESPN，编码f -肌动蛋白交联体espin；ARSG，编码芳基磺化酶G酶。20.
Usher syndrome (USH) represents a group of genetically heterogenous autosomal recessive disorders, characterized by combined vision and sensorineural hearing loss, and in some cases vestibular dysfunction. 1–3 It primarily affects the light-sensitive photoreceptor cells in the retina and the auditory hair cells in the cochlea. Vision loss in all cases is progressive, and manifests as retinitis pigmentosa (RP), characterized by the gradual degeneration of the photoreceptor cells. 4 Peripheral rod function is lost first, leading to night blindness and constricted visual fields, followed by the death of cones and severe visual impairment. There are currently no drugs or biological therapies proven to be effective in treating USH syndrome. Cochlear implantation, which bypasses the damaged hair cells and stimulates the primary auditory neurons directly, is an effective approach to alleviate the hearing impairment in patients. However, there is no remedy for the progressive loss of the photoreceptor neurons in the retina, and thus a critical unmet need exists to develop therapeutic strategies to prevent blindness in USH syndrome. The generation of animal models that faithfully mimic the human USH disorder, the timing of gene therapy interventions, the identification of correct target cells and patient selection are key factors in successfully reaching this goal.USH syndrome was named after Dr Charles Howard Usher, a Scottish ophthalmologist who described 69 patients with the disease in 1914. 5 As is commonly the case in medicine, the disease was first described much earlier (1858) in brothers suffering from blindness and deafness by von Gräfe 6 and was further characterized by his student, Liebreich, 7 3 years later in a larger population of patients. From its discovery until recently, USH syndrome and its subgroups were delineated by clinical characteristics. 8 Now the disease is recognized by symptomology and classified by genotyping. To date, there are at least 10 causative genes that are associated with USH syndrome, summarized in previous reviews. 1, 2, 9 In general, based on its diverse clinical symptoms, particularly the onset and severity of the sensorineural hearing impairment and the presence of vestibular dysfunction, USH syndrome is grouped into 3 clinical subtypes. Type I disease is associated with severe-to-profound prelingual hearing loss, vestibular abnormalities and prepubescent onset of RP symptoms. 10, 11 USH1 results from mutations in MYO7A (USH1B), HARMONIN (USH1C), CDH23 (USH1D), PCDH15 (USH1F), SANS (USH1G), and CIB2 (USH1J). Patients with type II disease display moderate-to-severe congenital hearing loss without vestibular dysfunction, and account for> 50% of all USH cases. Their RP symptoms generally begin in the second decade. 12 USH2 is caused by mutations in USH2A (USH2A), ADGRV1 (USH2C), and WHRN (USH2D). Patients with type III disease caused by mutations in CLRN1 (USH3A) gene have postlingual progressive hearing loss, variable vestibular dysfunction, and variable onset of RP that rapidly progresses to legal blindness by the fourth decade of life. 13–17 Mutations in the HARS gene (Histidyl-tRNA synthetase) are associated with the ultra-rare form USH3B. 18, 19 Other genes have been described in cases of atypical USH, including: CEP250 and CEP78, encoding members of the CEP family of centrosome-associated proteins; ESPN, encoding the F-actin cross-linker espin; ARSG, encoding the arylsulfatase G enzyme. 20