A Double-Masked, Randomized, Placebo-Controlled, Paired-Eye Study to Evaluate the Efficacy, Safety and Tolerability of Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Due to the c.2991+1655A>G (p.Cys998X) Mutation in the CEP290 Gene

The purpose of this double-masked, randomized, placebo-controlled, paired-eye study is to evaluate the efficacy, safety and tolerability of Sepofarsen in subjects with Leber Congenital Amaurosis (LCA) due to the c.2991+1655A>G (p.Cys998X) mutation in the CEP290.

开始日期2025-06-04

申办/合作机构

Laboratoires Théa SAS

NCT04855045

/ Unknown status临床2/3期

An Open-Label, Dose Escalation and Double-Masked, Randomized, Controlled Study to Evaluate the Safety and Tolerability of Sepofarsen in Pediatric Subjects <8 Years of Age With Leber Congenital Amaurosis Type 10 (LCA10) Due to the c.2991 +1655A>G (p.Cys998X) Mutation.

PQ-110-005 (BRIGHTEN) is an open-label, dose escalation and double-masked, randomized, controlled study evaluating safety and tolerability of sepofarsen administered via intravitreal (IVT) injection in pediatric subjects (<8 years of age) with LCA10 due to the c.2991+1655A>G mutation over 24 months of treatment.

开始日期2021-03-23

申办/合作机构

ProQR Therapeutics NV

NCT03913130

/ Terminated临床1/2期

An Open-Label, Extension Study to Evaluate the Safety, Tolerability, Efficacy and Pharmacokinetics of QR-110 in Subjects With Leber's Congenital Amaurosis (LCA) Due to the c.2991+1655A>G Mutation (p.Cys998X) in the CEP290 Gene

Subjects completing participation in study PQ-110-001 (EudraCT 2017-000813-22 / NCT03140969) will be given the opportunity to enroll into the extension study for continued dosing if available data support current and/or future benefits for the subject. Study PQ-110-002 will provide long-term safety, tolerability, pharmacokinetic (PK), and efficacy data of QR-110.

开始日期2019-05-13

申办/合作机构

Laboratoires Théa SAS

100 项与 Sepofarsen 相关的临床结果

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100 项与 Sepofarsen 相关的转化医学

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100 项与 Sepofarsen 相关的专利（医药）

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项与 Sepofarsen 相关的文献（医药）

2023-12-01·American journal of ophthalmology case reports

Durable vision improvement after a single intravitreal treatment with antisense oligonucleotide in CEP290-LCA: Replication in two eyes

作者: Wu, Vivian ; Girach, Aniz ; Ho, Allen C ; Viarbitskaya, Iryna ; Sumaroka, Alexander ; Swider, Malgorzata ; Cideciyan, Artur V ; Garafalo, Alexandra V ; Russell, Robert C ; Jacobson, Samuel G ; Schwartz, Michael R ; Roman, Alejandro J

Purpose:

An intravitreally injected antisense oligonucleotide, sepofarsen, was designed to modulate splicing within retinas of patients with severe vision loss due to deep intronic c.2991 + 1655A > G variant in the CEP290 gene. A previous report showed vision improvements following a single injection in one eye with unexpected durability lasting at least 15 months. The current study evaluated durability of efficacy beyond 15 months in the previously treated left eye. In addition, peak efficacy and durability were evaluated in the treatment-naive right eye, and re-injection of the left eye 4 years after the first injection.

Observations:

Visual function was evaluated with best corrected standard and low-luminance visual acuities, microperimetry, dark-adapted chromatic perimetry, and full-field sensitivity testing. Retinal structure was evaluated with OCT imaging. At the fovea, all visual function measures and IS/OS intensity of the OCT showed transient improvements peaking at 3-6 months, remaining better than baseline at ∼2 years, and returning to baseline by 3-4 years after each single injection.

Conclusions and Importance:

These results suggest that sepofarsen reinjection intervals may need to be longer than 2 years.

2022-06-01·Ophthalmology science

Restoration of Cone Sensitivity to Individuals with Congenital Photoreceptor Blindness within the Phase 1/2 Sepofarsen Trial

Article

作者: Drack, Arlene V ; Schwartz, Michael R ; Garafalo, Alexandra V ; Leroy, Bart P ; Russell, Stephen R ; Ho, Allen C ; Cideciyan, Artur V ; Swider, Malgorzata ; Jacobson, Samuel G ; Krishnan, Arun K ; Roman, Alejandro J ; Van Cauwenbergh, Caroline ; Girach, Aniz ; Wu, Vivian ; Sumaroka, Alexander

Purpose:

To understand consequences of reconstituting cone photoreceptor function in congenital binocular blindness resulting from mutations in the centrosomal protein 290 (CEP290) gene.

Design:

Phase 1b/2 open-label, multicenter, multiple-dose, dose-escalation trial.

Participants:

A homogeneous subgroup of 5 participants with light perception (LP) vision at the time of enrollment (age range, 15-41 years) selected for detailed analyses. Medical histories of 4 participants were consistent with congenital binocular blindness, whereas 1 participant showed evidence of spatial vision in early life that was later lost.

Intervention:

Participants received a single intravitreal injection of sepofarsen (160 or 320 μg) into the study eye.

Main Outcome Measures:

Full-field stimulus testing (FST), visual acuity (VA), and transient pupillary light reflex (TPLR) were measured at baseline and for 3 months after the injection.

Results:

All 5 participants with LP vision demonstrated severely abnormal FST and TPLR findings. At baseline, FST threshold estimates were 0.81 and 1.0 log cd/m² for control and study eyes, respectively. At 3 months, study eyes showed a large mean improvement of -1.75 log versus baseline (P < 0.001), whereas untreated control eyes were comparable with baseline. Blue minus red FST values were not different than 0 (P = 0.59), compatible with cone mediation of remnant vision. At baseline, TPLR response amplitude and latency estimates were 0.39 mm and 0.72 seconds, respectively, for control eyes, and 0.28 mm and 0.78 seconds, respectively, for study eyes. At 3 months, study eyes showed a mean improvement of 0.44 mm in amplitude and a mean acceleration of 0.29 seconds in latency versus baseline (P < 0.001), whereas control eyes showed no significant change versus baseline. Specialized tests performed in 1 participant confirmed and extended the standardized results from all 5 participants.

Conclusions:

By subjective and objective evidence, intravitreal sepofarsen provides improvement of light sensitivity for individuals with LP vision. However, translation of increased light sensitivity to improved spatial vision may occur preferentially in those with a history of visual experience during early neurodevelopment. Interventions for congenital lack of spatial vision in CEP290-associated Leber congenital amaurosis may lead to better results if performed before visual cortex maturity.

2022-05-01·Nature medicine1区 · 医学

Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial

1区 · 医学

Article

作者: Hoyng, Carel ; Ho, Allen C ; Schwartz, Michael R ; Adamson, Peter ; Leroy, Bart P ; Vanhonsebrouck, Eva ; Russell, Stephen R ; Collin, Rob W J ; Rodman, David ; Cideciyan, Artur V ; Platenburg, Gerard ; Han, Ian C ; Walshire, Jean ; Cheetham, Michael E ; den Hollander, Wilhelmina ; De Zaeytijd, Julie ; Jones, Eltanara ; Sumaroka, Alexander ; Asmus, Friedrich ; Martin, Mitchell ; Jacobson, Samuel G ; Pfeifer, Wanda L ; Powers, Christian A ; Garafalo, Alexandra V ; Drack, Arlene V ; Sohn, Elliott H ; Krishnan, Arun K ; Nerinckx, Fanny ; Girach, Aniz ; Dumitrescu, Alina V ; Van Cauwenbergh, Caroline ; Roman, Alejandro J

Abstract:

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit–risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.

项与 Sepofarsen 相关的新闻（医药）

2026-08-07

·中国生物器材网

视网膜色素变性研究的临床前模型hRHO点突变小鼠的介绍与研究进展

视网膜色素变性（RP）是一类以进行性感光细胞退化为特征的遗传性致盲眼病，其中hRHO基因突变是常染色体显性RP（adRP）的最常见病因。本文系统梳理hRHO点突变的致病机制与分类，重点介绍南模生物构建的hRHO-P23H、hRHO-D190Y、hRHO-C110R、hRHO-R135W等系列点突变小鼠模型，并以hRHO-P23H人源化小鼠模型的视网膜表型数据为例，展示其作为临床前CRO药效评价工具在ASO、基因编辑等创新疗法验证中的价值。 hRHO基因与视网膜色素变性视紫红质是视杆细胞中负责感光的关键G蛋白偶联受体。hRHO基因突变是导致常染色体显性视网膜色素变性（Autosomal Dominant Retinitis Pigmentosa, adRP）的最常见原因，在全球adRP病例中约占20%至30% [1]。目前已发现超过150种致病性RHO突变 [2]。这些突变多数为错义突变，导致蛋白质错误折叠、在内质网中异常聚集，进而引发内质网应激、未折叠蛋白反应，最终导致感光细胞凋亡和进行性视力丧失（图1）。这些突变主要分为两大类： · 功能获得型突变导致视紫红质蛋白错误折叠或功能异常，对视杆细胞产生毒性，诱发细胞凋亡，最终引起常染色体显性RP [1]。 · 功能缺失型突变导致无法合成功能性视紫红质，进而引起视杆细胞外段退化，通常表现为常染色体隐性RP。图1. 视紫红质突变可能导致的潜在致病后果示意图 hRHO-P23H：视网膜色素变性研究的经典遗传模型 hRHO-P23H是研究常染色体显性视网膜色素变性的关键模型。P23H突变是北美地区adRP最常见的病因，约占该地区adRP患者的10% [4]。这一错义突变导致视紫红质蛋白第23位的脯氨酸被组氨酸取代，引发蛋白质错误折叠和内质网应激。在分子机制层面，P23H突变导致视紫红质异常聚集并形成高分子量寡聚物 [5]。突变蛋白在内质网中积累，激活未折叠蛋白反应并最终触发光感受器细胞凋亡 [6]。研究表明，P23H视紫红质在杆状光感受器外段盘膜中形成致密荧光灶，破坏盘膜稳定性 [7]。 hRHO-P23H小鼠模型通过基因编辑技术构建，将小鼠内源性RHO基因替换为携带P23H突变的人源RHO基因。这些模型显示进行性视网膜变性，光感受器逐渐退化，为研究疾病机制提供了重要平台 [4]。其他RHO点突变模型（D190Y / C110R / R135W） hRHO-D190Y模型 D190Y突变位于视紫红质蛋白的第四个跨膜结构域，天冬氨酸190被酪氨酸取代。该突变在中国患者中被报道与严重表型相关 [8]。hRHO-D190Y小鼠模型通过基因编辑技术构建，其中小鼠内源性Rho基因被携带D190Y突变的人源RHO基因取代。该模型为研究这一特定突变的致病机制提供了工具。 hRHO-C110R模型 C110R突变导致第110位半胱氨酸被精氨酸取代，位于视紫红质的第二个胞外环 [9]。这一突变是少数几个有患者眼部病理研究的RHO突变之一。半胱氨酸残基在维持视紫红质结构稳定性中起关键作用，其突变可能影响二硫键形成和蛋白质正确折叠。C110和C187之间形成独特的二硫键对视紫红质结构至关重要。C110R模型有助于研究半胱氨酸残基在视紫红质功能中的作用。 hRHO-R135W模型 R135W突变是常染色体显性RP中相对常见的突变类型。在中国汉族大家系研究中，该突变与经典adRP表型相关，同时伴有异质性临床表现，包括不同的屈光不正、白内障、散光和视网膜前膜。分子遗传学研究显示，R135W突变在特定患者群体中频率较高。该突变通过全外显子组测序和Sanger测序在多个家系中被鉴定 [10]。 hRHO点突变模型：疾病机制研究的利器南模生物建立了完整的hRHO点突变模型体系，包括hRHO-P23H、hRHO-D190Y、hRHO-C110R和hRHO-R135W等模型。这些模型为研究RHO突变的致病机制、筛选潜在治疗药物和评估基因治疗策略提供了重要平台。我们的hRHO-P23H模型再现了人类患者中观察到的视网膜变性特征，包括光感受器外段结构破坏、突触连接减少和神经炎症反应。该模型显示快速神经视网膜变性，为研究RHO相关RP的病理机制提供了重要工具 [11]。 hRHO-P23H小鼠视网膜表型数据 hRHO-P23H小鼠的视网膜存在异常：hRHO-P23H雄性小鼠15周龄时，视网膜形态和结构出现了异常，呈现为视网膜外核层变薄。图2. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠的眼底形态、OCT检测和FFA检测结果 hRHO-P23H小鼠的视网膜结构和视紫红质蛋白表达异常：hRHO-P23H雄性小鼠15周龄时，视网膜结构和RHO表达出现了异常，呈现为视网膜外核层变薄，RHO蛋白表达减少。图3. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠的视网膜免疫组化染色结果 hRHO-P23H小鼠视网膜电图（ERG）存在异常：结果显示，与WT小鼠和hRHO小鼠相比，15周龄杂合hRHO-P23H小鼠的暗适应（Scotopic）a波与b波的振幅出现显著降低，而明适应（Photopic）a波的振幅暂未出现显著降低。图4. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠眼部ERG检测结果总结 hRHO-P23H杂合子小鼠在15周龄时视网膜外核层（ONL）明显变薄。病理染色发现感光细胞外核层和内核层均变薄，且视网膜视紫红质蛋白表达异常。视网膜电图ERG检测进一步表明，与野生型对照相比，该品系小鼠的暗适应a波、b波以及明适应a波振幅均显著降低，提示其视网膜功能存在缺陷。该hRHO-P23H人源化小鼠模型精准模拟了人类常染色体显性视网膜色素变性（adRP）的病理特征，是研究P23H突变导致视网膜退行性疾病的理想工具。作为临床前药物评价的"金标准"模型，它已成功应用于ASO药物、基因编辑疗法等创新治疗手段的疗效验证，为视网膜疾病的新药研发提供了强有力的支撑平台。研究进展：RHO相关adRP的治疗探索围绕RHO相关adRP，多条治疗路线正在推进。反义寡核苷酸（ASO）是目前临床进展较快的方向之一：QR-1123是一款针对P23H突变型mRNA设计的ASO，通过选择性降低突变型视紫红质表达、同时保留野生型视紫红质，已在P23H驱动的adRP患者中开展Ⅰ/Ⅱ期临床试验（NCT04123626） [12]。在基因编辑层面，多种策略仍处于临床前阶段：包括针对P23H突变的CRISPR-Cas9等位基因特异性编辑、Cas13介导的RNA编辑，以及meganuclease编辑等 [13]。参考文献： [1] McNamee SM, Chan NP, Akula M, et al. Preclinical dose response study shows NR2E3 can attenuate retinal degeneration in the retinitis pigmentosa mouse model RhoP23H+/. Gene Ther. 2024 May;31(5-6):255-262. doi: 10.1038/s41434-024-00440-6. [2] Kandoi S, Martinez C, Chen KX, et al. Disease modeling and pharmacological rescue of autosomal dominant retinitis pigmentosa associated with RHO copy number variation. Elife. 2024 Apr 25;12:RP90575. doi: 10.7554/eLife.90575. [3] Athanasiou D, Aguila M, Bellingham J, et al. The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy. Prog Retin Eye Res. 2018 Jan;62:1-23. doi: 10.1016/j.preteyeres.2017.10.002. [4] Barwick SR, Smith SB. Comparison of Mouse Models of Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation of Rhodopsin. Adv Exp Med Biol. 2023;1415:341-345. doi: 10.1007/978-3-031-27681-1_49. [5] Illing ME, Rajan RS, Bence NF, et al. A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. J Biol Chem. 2002 Sep 13;277(37):34150-60. doi: 10.1074/jbc.M204955200. [6] Gorbatyuk MS, Gorbatyuk OS, LaVail MM, et al. Functional rescue of P23H rhodopsin photoreceptors by gene delivery. Adv Exp Med Biol. 2012;723:191-7. doi: 10.1007/978-1-4614-0631-0_26. [7] Haeri M, Knox BE. Rhodopsin mutant P23H destabilizes rod photoreceptor disk membranes. PLoS One. 2012;7(1):e30101. doi: 10.1371/journal.pone.0030101. [8] Pan Z, Lu T, Zhang X, et al. Identification of two mutations of the RHO gene in two Chinese families with retinitis pigmentosa: correlation between genotype and phenotype. Mol Vis. 2012;18:3013-20. Epub 2012 Dec 14. [9] Zhou XE, Melcher K, Xu HE. Structure and activation of rhodopsin. Acta Pharmacol Sin. 2012 Mar;33(3):291-9. doi: 10.1038/aps.2011.171. [10] Wu Y, Guo Y, Yi J, et al. Heterozygous RHO p.R135W missense mutation in a large Han-Chinese family with retinitis pigmentosa and different refractive errors. Biosci Rep. 2019 Jul 12;39(7):BSR20182198. doi: 10.1042/BSR20182198. [11] Thompson SL, Crowder SM, Hekmatara M, et al. P23H rhodopsin aggregation in the ER causes synaptic protein imbalance in rod photoreceptors. bioRxiv [Preprint]. 2024 Dec 16:2024.10.18.619115. doi: 10.1101/2024.10.18.619115. [12] QR-1123 (sepofarsen-type antisense oligonucleotide) for P23H autosomal dominant retinitis pigmentosa, Phase 1/2 clinical trial NCT04123626. ClinicalTrials.gov. [13] Diakatou M, Manes G, Bocquet B, et al. Genome Editing as a Treatment for the Most Prevalent Causative Genes of Autosomal Dominant Retinitis Pigmentosa. Int J Mol Sci. 2019;20(10):2542. doi: 10.3390/ijms20102542. 关于我们上海南方模式生物科技股份有限公司（Shanghai Model Organisms Center, Inc.，简称"南模生物"），成立于2000年9月，是一家上交所科创板上市高科技生物公司（股票代码：688265），始终以编辑基因、解码生命为己任，专注于模式生物领域，打造了以基因修饰动物模型研发为核心，涵盖多物种模型构建、饲养繁育、表型分析、药物临床前评价等多个技术平台，致力于为全球高校、科研院所、制药企业等客户提供全方位、一体化的基因修饰动物模型产品解决方案。欢迎通过以下方式联系我们：微信公众号「南模生物SMOC」在线咨询拨打400-728-0660 发送邮件至marketing@modelorg.com 点击文末「阅读原文」图1. 视紫红质突变可能导致的潜在致病后果示意图图2. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠的眼底形态、OCT检测和FFA检测结果图2. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠的眼底形态、OCT检测和FFA检测结果图3. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠的视网膜免疫组化染色结果图4. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠眼部ERG检测结果

2026-08-07

·简书

hRHO-P23H等系列点突变小鼠：adRP机制研究与新药评价的人源化小鼠模型

视网膜色素变性（RP）是一类以进行性感光细胞退化为特征的遗传性致盲眼病，其中hRHO基因突变是常染色体显性RP（adRP）的最常见病因。本文系统梳理hRHO点突变的致病机制与分类，重点介绍南模生物构建的hRHO-P23H、hRHO-D190Y、hRHO-C110R、hRHO-R135W等系列点突变小鼠模型，并以hRHO-P23H人源化小鼠模型的视网膜表型数据为例，展示其作为临床前CRO药效评价工具在ASO、基因编辑等创新疗法验证中的价值。hRHO基因与视网膜色素变性视紫红质是视杆细胞中负责感光的关键G蛋白偶联受体。hRHO基因突变是导致常染色体显性视网膜色素变性（Autosomal Dominant Retinitis Pigmentosa, adRP）的最常见原因，在全球adRP病例中约占20%至30% [1]。目前已发现超过150种致病性RHO突变 [2]。这些突变多数为错义突变，导致蛋白质错误折叠、在内质网中异常聚集，进而引发内质网应激、未折叠蛋白反应，最终导致感光细胞凋亡和进行性视力丧失（图1）。这些突变主要分为两大类：· 功能获得型突变导致视紫红质蛋白错误折叠或功能异常，对视杆细胞产生毒性，诱发细胞凋亡，最终引起常染色体显性RP [1]。· 功能缺失型突变导致无法合成功能性视紫红质，进而引起视杆细胞外段退化，通常表现为常染色体隐性RP。图1. 视紫红质突变可能导致的潜在致病后果示意图 hRHO-P23H：视网膜色素变性研究的经典遗传模型hRHO-P23H是研究常染色体显性视网膜色素变性的关键模型。P23H突变是北美地区adRP最常见的病因，约占该地区adRP患者的10% [4]。这一错义突变导致视紫红质蛋白第23位的脯氨酸被组氨酸取代，引发蛋白质错误折叠和内质网应激。在分子机制层面，P23H突变导致视紫红质异常聚集并形成高分子量寡聚物 [5]。突变蛋白在内质网中积累，激活未折叠蛋白反应并最终触发光感受器细胞凋亡 [6]。研究表明，P23H视紫红质在杆状光感受器外段盘膜中形成致密荧光灶，破坏盘膜稳定性 [7]。hRHO-P23H小鼠模型通过基因编辑技术构建，将小鼠内源性RHO基因替换为携带P23H突变的人源RHO基因。这些模型显示进行性视网膜变性，光感受器逐渐退化，为研究疾病机制提供了重要平台 [4]。其他RHO点突变模型（D190Y / C110R / R135W）hRHO-D190Y模型D190Y突变位于视紫红质蛋白的第四个跨膜结构域，天冬氨酸190被酪氨酸取代。该突变在中国患者中被报道与严重表型相关 [8]。hRHO-D190Y小鼠模型通过基因编辑技术构建，其中小鼠内源性Rho基因被携带D190Y突变的人源RHO基因取代。该模型为研究这一特定突变的致病机制提供了工具。hRHO-C110R模型C110R突变导致第110位半胱氨酸被精氨酸取代，位于视紫红质的第二个胞外环 [9]。这一突变是少数几个有患者眼部病理研究的RHO突变之一。半胱氨酸残基在维持视紫红质结构稳定性中起关键作用，其突变可能影响二硫键形成和蛋白质正确折叠。C110和C187之间形成独特的二硫键对视紫红质结构至关重要。C110R模型有助于研究半胱氨酸残基在视紫红质功能中的作用。hRHO-R135W模型R135W突变是常染色体显性RP中相对常见的突变类型。在中国汉族大家系研究中，该突变与经典adRP表型相关，同时伴有异质性临床表现，包括不同的屈光不正、白内障、散光和视网膜前膜。分子遗传学研究显示，R135W突变在特定患者群体中频率较高。该突变通过全外显子组测序和Sanger测序在多个家系中被鉴定 [10]。hRHO点突变模型：疾病机制研究的利器南模生物建立了完整的hRHO点突变模型体系，包括hRHO-P23H、hRHO-D190Y、hRHO-C110R和hRHO-R135W等模型。这些模型为研究RHO突变的致病机制、筛选潜在治疗药物和评估基因治疗策略提供了重要平台。我们的hRHO-P23H模型再现了人类患者中观察到的视网膜变性特征，包括光感受器外段结构破坏、突触连接减少和神经炎症反应。该模型显示快速神经视网膜变性，为研究RHO相关RP的病理机制提供了重要工具 [11]。hRHO-P23H小鼠视网膜表型数据hRHO-P23H小鼠的视网膜存在异常：hRHO-P23H雄性小鼠15周龄时，视网膜形态和结构出现了异常，呈现为视网膜外核层变薄。图2. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠的眼底形态、OCT检测和FFA检测结果 hRHO-P23H小鼠的视网膜结构和视紫红质蛋白表达异常：hRHO-P23H雄性小鼠15周龄时，视网膜结构和RHO表达出现了异常，呈现为视网膜外核层变薄，RHO蛋白表达减少。图3. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠的视网膜免疫组化染色结果 hRHO-P23H小鼠视网膜电图（ERG）存在异常：结果显示，与WT小鼠和hRHO小鼠相比，15周龄杂合hRHO-P23H小鼠的暗适应（Scotopic）a波与b波的振幅出现显著降低，而明适应（Photopic）a波的振幅暂未出现显著降低。图4. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠眼部ERG检测结果总结hRHO-P23H杂合子小鼠在15周龄时视网膜外核层（ONL）明显变薄。病理染色发现感光细胞外核层和内核层均变薄，且视网膜视紫红质蛋白表达异常。视网膜电图ERG检测进一步表明，与野生型对照相比，该品系小鼠的暗适应a波、b波以及明适应a波振幅均显著降低，提示其视网膜功能存在缺陷。该hRHO-P23H人源化小鼠模型精准模拟了人类常染色体显性视网膜色素变性（adRP）的病理特征，是研究P23H突变导致视网膜退行性疾病的理想工具。作为临床前药物评价的"金标准"模型，它已成功应用于ASO药物、基因编辑疗法等创新治疗手段的疗效验证，为视网膜疾病的新药研发提供了强有力的支撑平台。研究进展：RHO相关adRP的治疗探索围绕RHO相关adRP，多条治疗路线正在推进。反义寡核苷酸（ASO）是目前临床进展较快的方向之一：QR-1123是一款针对P23H突变型mRNA设计的ASO，通过选择性降低突变型视紫红质表达、同时保留野生型视紫红质，已在P23H驱动的adRP患者中开展Ⅰ/Ⅱ期临床试验（NCT04123626） [12]。在基因编辑层面，多种策略仍处于临床前阶段：包括针对P23H突变的CRISPR-Cas9等位基因特异性编辑、Cas13介导的RNA编辑，以及meganuclease编辑等 [13]。参考文献：[1] McNamee SM, Chan NP, Akula M, et al. Preclinical dose response study shows NR2E3 can attenuate retinal degeneration in the retinitis pigmentosa mouse model RhoP23H+/. Gene Ther. 2024 May;31(5-6):255-262. doi: 10.1038/s41434-024-00440-6.[2] Kandoi S, Martinez C, Chen KX, et al. Disease modeling and pharmacological rescue of autosomal dominant retinitis pigmentosa associated with RHO copy number variation. Elife. 2024 Apr 25;12:RP90575. doi: 10.7554/eLife.90575.[3] Athanasiou D, Aguila M, Bellingham J, et al. The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy. Prog Retin Eye Res. 2018 Jan;62:1-23. doi: 10.1016/j.preteyeres.2017.10.002.[4] Barwick SR, Smith SB. Comparison of Mouse Models of Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation of Rhodopsin. Adv Exp Med Biol. 2023;1415:341-345. doi: 10.1007/978-3-031-27681-1_49.[5] Illing ME, Rajan RS, Bence NF, et al. A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. J Biol Chem. 2002 Sep 13;277(37):34150-60. doi: 10.1074/jbc.M204955200.[6] Gorbatyuk MS, Gorbatyuk OS, LaVail MM, et al. Functional rescue of P23H rhodopsin photoreceptors by gene delivery. Adv Exp Med Biol. 2012;723:191-7. doi: 10.1007/978-1-4614-0631-0_26.[7] Haeri M, Knox BE. Rhodopsin mutant P23H destabilizes rod photoreceptor disk membranes. PLoS One. 2012;7(1):e30101. doi: 10.1371/journal.pone.0030101.[8] Pan Z, Lu T, Zhang X, et al. Identification of two mutations of the RHO gene in two Chinese families with retinitis pigmentosa: correlation between genotype and phenotype. Mol Vis. 2012;18:3013-20. Epub 2012 Dec 14.[9] Zhou XE, Melcher K, Xu HE. Structure and activation of rhodopsin. Acta Pharmacol Sin. 2012 Mar;33(3):291-9. doi: 10.1038/aps.2011.171.[10] Wu Y, Guo Y, Yi J, et al. Heterozygous RHO p.R135W missense mutation in a large Han-Chinese family with retinitis pigmentosa and different refractive errors. Biosci Rep. 2019 Jul 12;39(7):BSR20182198. doi: 10.1042/BSR20182198.[11] Thompson SL, Crowder SM, Hekmatara M, et al. P23H rhodopsin aggregation in the ER causes synaptic protein imbalance in rod photoreceptors. bioRxiv [Preprint]. 2024 Dec 16:2024.10.18.619115. doi: 10.1101/2024.10.18.619115.[12] QR-1123 (sepofarsen-type antisense oligonucleotide) for P23H autosomal dominant retinitis pigmentosa, Phase 1/2 clinical trial NCT04123626. ClinicalTrials.gov.[13] Diakatou M, Manes G, Bocquet B, et al. Genome Editing as a Treatment for the Most Prevalent Causative Genes of Autosomal Dominant Retinitis Pigmentosa. Int J Mol Sci. 2019;20(10):2542. doi: 10.3390/ijms20102542.

2026-08-07

·今日头条

hRHO点突变小鼠：视网膜色素变性研究的"金标准"临床前模型

视网膜色素变性（RP）是一类以进行性感光细胞退化为特征的遗传性致盲眼病，其中hRHO基因突变是常染色体显性RP（adRP）的最常见病因。本文系统梳理hRHO点突变的致病机制与分类，重点介绍南模生物构建的hRHO-P23H、hRHO-D190Y、hRHO-C110R、hRHO-R135W等系列点突变小鼠模型，并以hRHO-P23H 人源化小鼠模型的视网膜表型数据为例，展示其作为临床前CRO 药效评价工具在ASO、基因编辑等创新疗法验证中的价值。 hRHO基因与视网膜色素变性视紫红质是视杆细胞中负责感光的关键G蛋白偶联受体。hRHO基因突变是导致常染色体显性视网膜色素变性（Autosomal Dominant Retinitis Pigmentosa, adRP）的最常见原因，在全球adRP病例中约占20%至30% [1]。目前已发现超过150种致病性RHO突变 [2]。这些突变多数为错义突变，导致蛋白质错误折叠、在内质网中异常聚集，进而引发内质网应激、未折叠蛋白反应，最终导致感光细胞凋亡和进行性视力丧失（图1）。这些突变主要分为两大类： · 功能获得型突变导致视紫红质蛋白错误折叠或功能异常，对视杆细胞产生毒性，诱发细胞凋亡，最终引起常染色体显性RP [1]。 · 功能缺失型突变导致无法合成功能性视紫红质，进而引起视杆细胞外段退化，通常表现为常染色体隐性RP。图1. 视紫红质突变可能导致的潜在致病后果示意图 hRHO-P23H：视网膜色素变性研究的经典遗传模型 hRHO-P23H是研究常染色体显性视网膜色素变性的关键模型。P23H突变是北美地区adRP最常见的病因，约占该地区adRP患者的10% [4]。这一错义突变导致视紫红质蛋白第23位的脯氨酸被组氨酸取代，引发蛋白质错误折叠和内质网应激。在分子机制层面，P23H突变导致视紫红质异常聚集并形成高分子量寡聚物 [5]。突变蛋白在内质网中积累，激活未折叠蛋白反应并最终触发光感受器细胞凋亡 [6]。研究表明，P23H视紫红质在杆状光感受器外段盘膜中形成致密荧光灶，破坏盘膜稳定性 [7]。 hRHO-P23H小鼠模型通过基因编辑技术构建，将小鼠内源性RHO基因替换为携带P23H突变的人源RHO基因。这些模型显示进行性视网膜变性，光感受器逐渐退化，为研究疾病机制提供了重要平台 [4]。其他RHO点突变模型（D190Y / C110R / R135W） hRHO-D190Y模型 D190Y突变位于视紫红质蛋白的第四个跨膜结构域，天冬氨酸190被酪氨酸取代。该突变在中国患者中被报道与严重表型相关 [8]。hRHO-D190Y小鼠模型通过基因编辑技术构建，其中小鼠内源性Rho基因被携带D190Y突变的人源RHO基因取代。该模型为研究这一特定突变的致病机制提供了工具。 hRHO-C110R模型 C110R突变导致第110位半胱氨酸被精氨酸取代，位于视紫红质的第二个胞外环 [9]。这一突变是少数几个有患者眼部病理研究的RHO突变之一。半胱氨酸残基在维持视紫红质结构稳定性中起关键作用，其突变可能影响二硫键形成和蛋白质正确折叠。C110和C187之间形成独特的二硫键对视紫红质结构至关重要。C110R模型有助于研究半胱氨酸残基在视紫红质功能中的作用。 hRHO-R135W模型 R135W突变是常染色体显性RP中相对常见的突变类型。在中国汉族大家系研究中，该突变与经典adRP表型相关，同时伴有异质性临床表现，包括不同的屈光不正、白内障、散光和视网膜前膜。分子遗传学研究显示，R135W突变在特定患者群体中频率较高。该突变通过全外显子组测序和Sanger测序在多个家系中被鉴定 [10]。 hRHO点突变模型：疾病机制研究的利器南模生物建立了完整的hRHO点突变模型体系，包括hRHO-P23H、hRHO-D190Y、hRHO-C110R和hRHO-R135W等模型。这些模型为研究RHO突变的致病机制、筛选潜在治疗药物和评估基因治疗策略提供了重要平台。我们的hRHO-P23H模型再现了人类患者中观察到的视网膜变性特征，包括光感受器外段结构破坏、突触连接减少和神经炎症反应。该模型显示快速神经视网膜变性，为研究RHO相关RP的病理机制提供了重要工具 [11]。 hRHO-P23H小鼠视网膜表型数据 hRHO-P23H小鼠的视网膜存在异常：hRHO-P23H雄性小鼠15周龄时，视网膜形态和结构出现了异常，呈现为视网膜外核层变薄。图2. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠的眼底形态、OCT检测和FFA检测结果 hRHO-P23H小鼠的视网膜结构和视紫红质蛋白表达异常：hRHO-P23H雄性小鼠15周龄时，视网膜结构和RHO表达出现了异常，呈现为视网膜外核层变薄，RHO蛋白表达减少。图3. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠的视网膜免疫组化染色结果 hRHO-P23H小鼠视网膜电图（ERG）存在异常：结果显示，与WT小鼠和hRHO小鼠相比，15周龄杂合hRHO-P23H小鼠的暗适应（Scotopic）a波与b波的振幅出现显著降低，而明适应（Photopic）a波的振幅暂未出现显著降低。图4. 野生型小鼠（WT）、hRHO小鼠和杂合hRHO-P23H小鼠眼部ERG检测结果总结 hRHO-P23H杂合子小鼠在15周龄时视网膜外核层（ONL）明显变薄。病理染色发现感光细胞外核层和内核层均变薄，且视网膜视紫红质蛋白表达异常。视网膜电图ERG检测进一步表明，与野生型对照相比，该品系小鼠的暗适应a波、b波以及明适应a波振幅均显著降低，提示其视网膜功能存在缺陷。该hRHO-P23H人源化小鼠模型精准模拟了人类常染色体显性视网膜色素变性（adRP）的病理特征，是研究P23H突变导致视网膜退行性疾病的理想工具。作为临床前药物评价的"金标准"模型，它已成功应用于ASO药物、基因编辑疗法等创新治疗手段的疗效验证，为视网膜疾病的新药研发提供了强有力的支撑平台。研究进展：RHO相关adRP的治疗探索围绕RHO相关adRP，多条治疗路线正在推进。反义寡核苷酸（ASO）是目前临床进展较快的方向之一：QR-1123是一款针对P23H突变型mRNA设计的ASO，通过选择性降低突变型视紫红质表达、同时保留野生型视紫红质，已在P23H驱动的adRP患者中开展Ⅰ/Ⅱ期临床试验（NCT04123626） [12]。在基因编辑层面，多种策略仍处于临床前阶段：包括针对P23H突变的CRISPR-Cas9等位基因特异性编辑、Cas13介导的RNA编辑，以及meganuclease编辑等 [13]。参考文献： [1] McNamee SM, Chan NP, Akula M, et al. Preclinical dose response study shows NR2E3 can attenuate retinal degeneration in the retinitis pigmentosa mouse model RhoP23H+/. Gene Ther. 2024 May;31(5-6):255-262. doi: 10.1038/s41434-024-00440-6. [2] Kandoi S, Martinez C, Chen KX, et al. Disease modeling and pharmacological rescue of autosomal dominant retinitis pigmentosa associated with RHO copy number variation. Elife. 2024 Apr 25;12:RP90575. doi: 10.7554/eLife.90575. [3] Athanasiou D, Aguila M, Bellingham J, et al. The Molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy. Prog Retin Eye Res. 2018 Jan;62:1-23. doi: 10.1016/j.preteyeres.2017.10.002. [4] Barwick SR, Smith SB. Comparison of Mouse Models of Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation of Rhodopsin. Adv Exp Med Biol. 2023;1415:341-345. doi: 10.1007/978-3-031-27681-1_49. [5] Illing ME, Rajan RS, Bence NF, et al. A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. J Biol Chem. 2002 Sep 13;277(37):34150-60. doi: 10.1074/jbc.M204955200. [6] Gorbatyuk MS, Gorbatyuk OS, LaVail MM, et al. Functional rescue of P23H rhodopsin photoreceptors by gene delivery. Adv Exp Med Biol. 2012;723:191-7. doi: 10.1007/978-1-4614-0631-0_26. [7] Haeri M, Knox BE. Rhodopsin mutant P23H destabilizes rod photoreceptor disk membranes. PLoS One. 2012;7(1):e30101. doi: 10.1371/journal.pone.0030101. [8] Pan Z, Lu T, Zhang X, et al. Identification of two mutations of the RHO gene in two Chinese families with retinitis pigmentosa: correlation between genotype and phenotype. Mol Vis. 2012;18:3013-20. Epub 2012 Dec 14. [9] Zhou XE, Melcher K, Xu HE. Structure and activation of rhodopsin. Acta Pharmacol Sin. 2012 Mar;33(3):291-9. doi: 10.1038/aps.2011.171. [10] Wu Y, Guo Y, Yi J, et al. Heterozygous RHO p.R135W missense mutation in a large Han-Chinese family with retinitis pigmentosa and different refractive errors. Biosci Rep. 2019 Jul 12;39(7):BSR20182198. doi: 10.1042/BSR20182198. [11] Thompson SL, Crowder SM, Hekmatara M, et al. P23H rhodopsin aggregation in the ER causes synaptic protein imbalance in rod photoreceptors. bioRxiv [Preprint]. 2024 Dec 16:2024.10.18.619115. doi: 10.1101/2024.10.18.619115. [12] QR-1123 (sepofarsen-type antisense oligonucleotide) for P23H autosomal dominant retinitis pigmentosa, Phase 1/2 clinical trial NCT04123626. ClinicalTrials.gov. [13] Diakatou M, Manes G, Bocquet B, et al. Genome Editing as a Treatment for the Most Prevalent Causative Genes of Autosomal Dominant Retinitis Pigmentosa. Int J Mol Sci. 2019;20(10):2542. doi: 10.3390/ijms20102542. 关于我们上海南方模式生物科技股份有限公司（Shanghai Model Organisms Center, Inc.，简称"南模生物"），成立于2000年9月，是一家上交所科创板上市高科技生物公司（股票代码：688265），始终以编辑基因、解码生命为己任，专注于模式生物领域，打造了以基因修饰动物模型研发为核心，涵盖多物种模型构建、饲养繁育、表型分析、药物临床前评价等多个技术平台，致力于为全球高校、科研院所、制药企业等客户提供全方位、一体化的基因修饰动物模型产品解决方案。欢迎通过以下方式联系我们：微信公众号「南模生物SMOC」在线咨询

100 项与 Sepofarsen 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D12488	-	-	DB16327

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适应症	最高研发状态	国家/地区	公司	日期
视网膜变性疾病	临床3期	比利时	ProQR Therapeutics NV	2021-03-23
视网膜变性疾病	临床3期	巴西	ProQR Therapeutics NV	2021-03-23
视网膜变性疾病	临床3期	加拿大	ProQR Therapeutics NV	2021-03-23
视网膜变性疾病	临床3期	德国	ProQR Therapeutics NV	2021-03-23
视网膜变性疾病	临床3期	意大利	ProQR Therapeutics NV	2021-03-23
视网膜变性疾病	临床3期	荷兰	ProQR Therapeutics NV	2021-03-23
视网膜变性疾病	临床3期	英国	ProQR Therapeutics NV	2021-03-23
失明	临床3期	美国	ProQR Therapeutics NV	2019-04-04
失明	临床3期	比利时	ProQR Therapeutics NV	2019-04-04
失明	临床3期	巴西	ProQR Therapeutics NV	2019-04-04

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03913143 (ILLUMINATE, ARVO2026)	临床3期	莱伯先天性黑内障10型 CEP290-associated	15	Sepofarsen	膚淵壓構簾鑰顧餘網築(簾鏇醖網製夢簾廠獵夢) = 顧構積製醖糧艱鬱積構窪構鹽淵鏇願膚繭夢願 (襯鏇餘築簾餘範艱觸憲 ) 更多	积极	2026-05-03
				Sham injection	膚淵壓構簾鑰顧餘網築(簾鏇醖網製夢簾廠獵夢) = 繭齋壓獵齋築遞鏇繭襯窪構鹽淵鏇願膚繭夢願 (襯鏇餘築簾餘範艱觸憲 ) 更多
NCT06891443 (HYPERION, ARVO2026)	临床3期	莱伯先天性黑内障10型	62	Sepofarsen (Pediatric (<18 years))	顧構築願衊醖網鏇網蓋(鹽遞艱製鏇壓淵顧繭淵) = Most AEs were mild and related to the injection procedure 壓選夢廠艱鬱廠願鹽衊 (網憲選襯襯獵衊範蓋窪 )	积极	2026-05-03
				Sepofarsen (Adult (≥18 years))
NCT03913130 (INSIGHT, CTgov)	临床1/2期	失明 \| 莱伯先天性黑内障10型	9	QR-110	築糧遞衊範淵繭構夢醖 = 構願願衊築遞簾願窪積衊簾獵製淵遞鏇繭遞衊 (窪觸廠醖齋廠願窪憲餘, 遞鏇製夢鹽膚製範襯鑰 ~ 齋簾選蓋膚淵艱獵鏇齋) 更多	-	2023-01-04
NCT03140969 (Pubmed \| Nat Med)	临床1/2期	莱伯先天性黑内障10型	11	sepofarsen (Untreated eye)	鹽繭積廠獵糧遞鑰鹹築(選製壓襯遞蓋醖糧遞鑰) = Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. 積夢築鏇齋齋顧遞製製 (窪獵鹽窪窪選觸餘繭顧 ) 更多	积极	2022-04-04
EURETINA2021	N/A	莱伯先天性黑蒙	-	Sepofarsen 160 µg	鑰簾齋選繭齋製願淵醖(選鬱壓醖製選選範鑰鬱) = 觸夢醖鹽築顧選鑰鏇膚襯觸鹹淵鬱積構構鹹膚 (簾簾窪鬱鏇築選廠鹹蓋 ) 更多	-	2021-09-01
				Sepofarsen 80 µg	鑰簾齋選繭齋製願淵醖(選鬱壓醖製選選範鑰鬱) = 鹹鹽觸鹽蓋膚製鬱膚願襯觸鹹淵鬱積構構鹹膚 (簾簾窪鬱鏇築選廠鹹蓋 ) 更多
NCT03913130 (ARVO2021)	临床1/2期	莱伯先天性黑内障10型	9	Sepofarsen	選醖選蓋鏇衊製鏇獵淵(艱鬱鹹壓夢壓鹽壓積顧) = One patient developed cataract at Month 9 in the second treated eye 鑰窪繭網鏇窪鹹鬱鑰鑰 (鏇遞鏇鏇糧鹽鏇艱簾蓋 )	-	2021-06-01
NCT03140969 (CEP290, AAO2020)	临床1/2期	莱伯先天性黑内障10型 p.Cys998X mutation in the CEP290 gene	11	Sepofarsen 320/160-µg	選膚憲築繭糧鹽築窪簾(鑰範鬱構窪夢夢觸襯繭) = Reported cases of cataract were 3 in the 160/80-µg group and 5 in the 320/160-µg group 觸夢獵遞製蓋構鏇願獵 (憲鑰衊網膚膚壓蓋淵夢 ) 更多	积极	2020-11-13
NCT03140969 (ARVO2020)	临床1/2期	莱伯先天性黑蒙	11	sepofarsen 160/80 µg	衊憲願鏇繭蓋獵膚築簾(觸餘憲壓膚選齋醖醖膚) = Although sepofarsen treatment is associated with cataract development, it is well tolerated and shows improvement in BCVA, FST, and mobility course. The 160/80 µg dose has a more favorable benefit:risk profile than 320/160 µg 齋構顧衊構獵範選壓鹽 (製壓壓壓範艱醖鏇繭製 ) 更多	-	2020-06-01
				sepofarsen 320/160 µg
NCT03140969 (PQ-110-001, GlobeNewswire) 人工标引	临床1/2期	莱伯先天性黑内障10型	11	sepofarsen	窪蓋製築齋壓鏇選繭網(構淵選廠鏇餘壓製構願) = 淵範膚顧簾壓憲選鑰範鏇範襯夢窪醖膚壓鏇蓋 (淵窪壓範願餘鑰壓鏇膚 ) 更多	积极	2019-10-10
				Placebo	窪蓋製築齋壓鏇選繭網(構淵選廠鏇餘壓製構願) = 鹽築糧糧廠糧顧餘齋觸鏇範襯夢窪醖膚壓鏇蓋 (淵窪壓範願餘鑰壓鏇膚 ) 更多
NCT03140969 (CEP290, ARVO2019)	临床1/2期	莱伯先天性黑蒙	10	QR-110 160/80 µg	繭製製鹹範鹹顧鬱遞簾(鑰範壓範遞醖淵淵壓遞) = results also demonstrated greater stability 襯鏇繭襯蓋衊鬱鏇齋鹹 (衊餘廠鏇夢繭齋齋廠積 )	积极	2019-07-01
				QR-110 320/160 µg