ABCA4

Tinlarebant is Belite Bio’s orally administered tablet intended to slow disease progression in patients affected with Stargardt Disease (STGD1) and Geographic Atrophy (GA) in advanced Dry Age-related Macular Degeneration (Dry AMD) Data from a 24-month Phase 2 trial in adolescent STGD1 subjects showed a sustained lower atrophic lesion growth in Tinlarebant-treated subjects compared to ProgStar participants possessing similar baseline characteristics (aged ≤18 years) (p<0.001) In the Phase 2 trial, 42% of Tinlarebant-treated subjects (5 out of 12) did not develop atrophic retinal lesions during the 24-month treatment period Enrollment of a pivotal global Phase 3 trial of Tinlarebant in adolescent STGD1 subjects (“DRAGON”) has been completed with 104 subjects across 11 countries with interim data expected in 4Q 2024 Tinlarebant has been granted Orphan Drug Designation in Japan for the treatment of STGD1 A global Phase 3 trial in GA (“PHOENIX”) is ongoing SAN DIEGO, March 22, 2024 (GLOBE NEWSWIRE) -- Belite Bio, LLC (NASDAQ: BLTE) (“Belite Bio” or the “Company”), a clinical-stage biopharmaceutical drug development company focused on advancing novel therapeutics targeting degenerative retinal diseases that have significant unmet medical needs, today announces its submission to the Pharmaceuticals and Medical Devices Agency (PMDA) to initiate a clinical trial of Tinlarebant in adolescent STGD1 in Japan (“DRAGON II”). The DRAGON II trial is a combination of Phase 1b open-label study to evaluate the pharmacokinetics and pharmacodynamics of Tinlarebant in Japanese adolescent STGD1 subjects and a Phase 2/3, global, multicenter, double-masked, placebo-controlled, randomized study designed to evaluate the efficacy, safety and tolerability of Tinlarebant in adolescent STGD1 subjects. Approximately 60 subjects, aged 12 to 20 years old, including approximately 10 Japanese subjects, are targeted for enrollment in the Phase 2/3 portion of the trial with a 1:1 randomization (tinlarebant:placebo). The data from Japanese subjects is intended to facilitate future NDA applications in Japan. About Tinlarebant (a/k/a LBS-008) Tinlarebant is a novel oral therapy that is intended to reduce the accumulation of vitamin A-based toxins (known as bisretinoids) that cause retinal disease in STGD1 and also contribute to disease progression in GA, or advanced Dry AMD. Bisretinoids are by-products of the visual cycle, which is dependent on the supply of vitamin A (retinol) to the eye. Tinlarebant works by reducing and maintaining levels of serum retinol binding protein 4 (RBP4), the sole carrier protein for retinol transport from the liver to the eye. By modulating the amount of retinol entering the eye, Tinlarebant reduces the formation of bisretinoids. Tinlarebant has been granted Fast Track Designation and Rare Pediatric Disease designation in the U.S., and Orphan Drug Designation in the U.S., Europe, and Japan for the treatment of STGD1. Stargardt Disease (STGD1) STGD1 is the most common inherited retinal dystrophy (causing blurring or loss of central vision) in both adults and children. The disease is caused by mutations in a retina-specific gene (ABCA4), which results in progressive accumulation of bisretinoids leading to retinal cell death and progressive loss of central vision. The fluorescent properties of bisretinoids and the development of retinal imaging systems have helped ophthalmologists identify and monitor disease progression. Currently, there are no FDA approved treatments for STGD1. Importantly, STGD1 and GA, or advanced Dry AMD, share a similar pathophysiology, which is characterized by the excessive accumulation of bisretinoids, retinal cell death, and progressive loss of vision. Vision loss occurs slowly, despite peripheral expansion of “dead retina,” until the disease reaches the center of the eye (the macula). Therefore, Belite Bio is evaluating safety and efficacy of Tinlarebant in GA patients in a 2-year Phase 3 study (PHOENIX). GA in advanced Dry Age-related Macular Degeneration (Dry AMD) Dry AMD is a leading cause of vision loss in older adults. Geographic Atrophy, or GA, is the advanced stage of AMD. Currently, there are no FDA approved orally administered treatments for GA and no FDA approved therapies for the other stages of Dry AMD other than GA. There are an estimated 20 million AMD patients in the U.S. and over 196 million patients worldwide with an estimated global direct healthcare cost of US$255 billion. About Belite Bio Belite Bio is a clinical-stage biopharmaceutical drug development company focused on advancing novel therapeutics targeting retinal degenerative eye diseases which have significant unmet medical needs such as (i) atrophic age-related macular degeneration (AMD), commonly known as Geographic Atrophy (GA) in advanced dry AMD, and (ii) autosomal recessive Stargardt disease type 1, or STGD1, in addition to specific metabolic diseases. For more information, follow us on Twitter, Instagram, LinkedIn, Facebook or visit us at . Important Cautions Regarding Forward Looking Statements This press release contains forward-looking statements about future expectations and plans, as well as other statements regarding matters that are not historical facts. These statements include but are not limited to statements regarding the potential implications of clinical data for patients, and Belite Bio’s advancement of, and anticipated preclinical activities, clinical development, regulatory milestones, and commercialization of its product candidates, and any other statements containing the words “expect”, “hope” and similar expressions. Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including but not limited to Belite Bio’s ability to demonstrate the safety and efficacy of its drug candidates; the clinical results for its drug candidates, which may not support further development or regulatory approval; the timing to complete relevant clinical trials and/or to receive the interim/final data of such clinical trials; the content and timing of decisions made by the relevant regulatory authorities regarding regulatory approval of Belite Bio’s drug candidates; the potential efficacy of Tinlarebant, as well as those risks more fully discussed in the “Risk Factors” section in Belite Bio’s filings with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Belite Bio, and Belite Bio undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law. Media and Investor Relations Contact: Jennifer Wu /ir@belitebio.com Julie Fallon / belite@argotpartners.com

▎药明康德内容团队编辑本期看点1. “明星”小分子ziftomenib联合标准治疗的早期数据亮眼，特定初治急性髓系白血病（AML）患者100%获得了完全缓解（CR）。2. 用于治疗遗传性血管水肿（HAE）的在研体内CRISPR基因编辑疗法NTLA-2002早期临床数据亮眼，单次给药后使所有患者的月度发作率平均下降了95%。3. 首个获美国FDA许可进入临床试验的RNA外显子编辑疗法ACDN-01被授予快速通道资格。药明康德内容团队整理Ziftomenib：公布1期临床试验数据Kura Oncology公司公布了ziftomenib联合标准治疗，包括阿糖胞苷/达柔比星（7+3）和维奈托克/阿扎胞苷（ven/aza），治疗NPM1突变型（NPM1-m）和KMT2A重排型（KMT2A-r）急性髓系白血病患者的1期临床试验的初步数据。Ziftomenib是一种针对menin与KMT2A/MLL蛋白复合体之间相互作用的在研候选药物，用于治疗有高度未满足需求，携带特定基因突变的AML患者。在临床前模型中，ziftomenib抑制了KMT2A/MLL蛋白复合体，并表现出强大的抗白血病活性。Ziftomenib已获得FDA授予的孤儿药资格，用于治疗AML。这款在研新药曾被猎药人网站（drughunter.com）列为2022年度10大“明星”小分子之一。截至2024年1月11日的数据，在新诊断的NPM1-m型和KMT2A-r型AML患者中，接受ziftomenib联合7+3治疗的CR率为100%；未接受过menin抑制剂治疗的难治/复发（R/R）性AML患者接受ziftomenib联合ven/aza治疗，CR/完全缓解伴部分血液学恢复（CRh）率为56%。安全性方面，连续每天服用200 mg ziftomenib的耐受性良好，其安全性与基础疾病和主要治疗方法的特征一致。NTLA-2002：公布1期临床试验的中期数据Intellia Therapeutics公司在《新英格兰医学杂志》（NEJM）上公布了其在研体内CRISPR基因编辑疗法NTLA-2002的1/2期临床试验的中期分析结果。NTLA-2002旨在使用CRISPR/Cas9技术对激肽释放酶B1（KLKB1）基因进行编辑，该基因负责编码激肽释放酶前体蛋白。通过让KLKB1失活，NTLA-2002可永久性降低激肽释放酶活性，以达到治愈HAE的目的。NTLA-2002包含靶向致病基因的指导RNA（gRNA），和编码Cas9酶的mRNA，它们共同开展精准编辑。结果显示，在最近一次随访中，单次给药NTLA-2002使所有患者（n=10）的HAE月度发作率平均下降了95%；在16周的主要观察期后，所有血浆激肽（kallikrein）水平降低超过60%以上的患者（n=9）仍然完全没有发作，最长的无发作间隔期已达13.0个月，并且还在持续；在所有在使用NTLA-2002后停止长期HAE预防治疗的患者（n=6）中，自停止治疗后还没有报告过HAE发作。此外，NTLA-2002在所有剂量水平上都有良好的耐受性。报告的最常见的不良事件是轻度、短暂的输液相关反应和疲劳。ACDN-01：IND申请获得FDA许可Ascidian Therapeutics公司宣布其在研RNA外显子编辑疗法ACDN-01的IND申请已经获得美国FDA的许可，并被授予快速通道资格。ACDN-01是一种在体内编辑RNA外显子的RNA编辑疗法。它通过单一载体递送，已在非人类灵长类动物的体内实验以及人类视网膜的体外实验中显示出有效且持久的RNA外显子编辑。与其它只修改一个RNA碱基的RNA编辑器不同，ACDN-01的独特之处在于能够重新书写RNA序列，将导致疾病的RNA序列替换为功能正常的RNA序列，具有使用一种疗法，治疗多种基因突变导致的Stargardt病的潜力。此外，RNA编辑疗法与基于CRISPR的基因组编辑疗法相比，由于不会对基因组序列产生永久影响，可能具有更高的安全性。新闻稿指出，ACDN-01是首个获美国FDA许可进入临床试验的RNA外显子编辑疗法，并且是首款专门针对Stargardt病遗传起源的临床期治疗方法。Ascidian预计在2024年上半年开始招募参与ACDN-01针对Stargardt病及其他ABCA4相关视网膜病变的1/2期临床试验STELLAR的患者。JAG201：IND申请获得FDA许可Jaguar Gene Therapy公司宣布，美国FDA已经批准了其用于治疗遗传性自闭症谱系障碍（ASD）和Phelan-McDermid综合征（PMS）的基因疗法JAG201的IND申请。JAG201旨在通过AAV9载体提供SHANK3基因的功能拷贝，持久地恢复学习和记忆所需的突触功能，从而从根本上治疗ASD和PMS。啮齿动物和非人灵长类动物的临床前研究表明，递送功能性SHANK3可改善神经行为、认知和运动功能异常。该公司计划于2024年下半年在美国启动一项1期试验，针对SHANK3突变或缺失的ASD或PMS成人患者。Deltacel：公布1期临床试验中首例患者的数据Kiromic BioPharma公司公布了其在研γ-δ T细胞（GDT）疗法Deltacel用于治疗转移性非小细胞肺癌（NSCLC）的1期临床试验的积极初步数据，该疗法在首例患者中展现出良好的早期疗效结果。Deltacel是一种同种异体细胞治疗产品，由未经修饰的供体来源GDT组成。Deltacel旨在利用GDT的天然效力靶向实体瘤，最初的临床开发重点是NSCLC（约占肺癌病例的80%至85%）。两项临床前研究的数据表明，Deltacel与低剂量放射治疗相结合具有良好的安全性和有效性。积极的初步证据证明了Deltacel在控制NSCLC生长方面的疗效。Deltacel的耐受性仍然良好，进一步证实早期安全性评估结果。首例患者在比佛利山癌症中心（BHCC）接受了治疗，并在开始治疗前三天被确诊为病情进展活跃的患者。接受Deltacel治疗六周后，CT扫描证实了此患者的病情稳定，初步的无进展生存期为一个半月。Risvodetinib：公布1期临床试验数据Inhibikase Therapeutics公司公布了其c-Abl抑制剂risvodetinib治疗老年帕金森病（PD）患者的1期临床试验的数据。结果显示，risvodetinib单次或多次给药在所有受试者中表现出良好的安全性和耐受性。健康受试者中未出现严重不良事件，服用抗PD药物的PD患者也未出现症状恶化。该公司正继续积极招募患者参加其2期试验，以评估risvodetinib对未经治疗的帕金森病患者的治疗效果。ARM210（S48168）：公布1b期临床试验数据ARMGO Pharma公司公布了其靶向ryanodine受体钙释放通道（RyR）的小分子药物ARM210（又称S48168）的1b期研究结果，该药拟用于治疗一种罕见的肌肉疾病——ryanodine受体1型相关肌病（RYR1-RM）。该1b期研究证实了每天服用120 mg和200 mg ARM210在RYR1-RM患者中的安全性和耐受性，并首次在临床上展现了每日服用200 mg ARM210可改善患者疲劳和近端肌力的迹象。此外，该研究还证实了ARM210能够通过修复由突变的RyR1通道造成的细胞内钙泄漏以恢复肌肉功能的作用机制。EC5026：启动1b期临床试验EicOsis Human Health宣布启动一项1b期多剂量递增试验，以评估其小分子候选药物EC5026的安全性。EC5026是一种强效、高选择性的可溶性环氧化物水解酶（sEH）抑制剂，在调节信号脂质的代谢、响应由创伤或疾病引起的炎症和其他应激反应方面发挥着至关重要的作用。通过抑制sEH，EC5026能阻止天然镇痛和抗炎脂肪酸的分解，从而缓解疼痛，是一种治疗中度至重度疼痛的潜在非阿片类药物。临床前研究表明，EC5026不会产生镇静或其他不良行为，也没有成瘾迹象。VTR-297：IND申请获得FDA许可Vanda Pharmaceuticals公司宣布，美国FDA已经批准了其小分子组蛋白脱乙酰酶（HDAC）抑制剂VTR-297用于治疗甲癣的IND申请。VTR-297具有抗皮癣菌和真菌的活性，最开始是作为一种抗真菌抗生素从酵母菌种Streptomyces hygroscopicus中被分离出来，于1976年首次被描述。自2014年以来，美国FDA尚未批准任何新的甲癣治疗方法。启动VTR-297治疗甲癣的临床研究是研究和开发治疗这种常见疾病的潜在新疗法的一个重要里程碑。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看）[1] Ascidian Therapeutics Announces First-Ever IND for an RNA Exon Editor as FDA Approves Trial Plan and Fast Tracks ACDN-01 in Stargardt Disease and Other ABCA4 Retinopathies. Retrieved January 30, 2024, from https://www.prnewswire.com/news-releases/ascidian-therapeutics-announces-first-ever-ind-for-an-rna-exon-editor-as-fda-approves-trial-plan-and-fast-tracks-acdn-01-in-stargardt-disease-and-other-abca4-retinopathies-302046287.html[2] ARMGO Pharma Publishes Positive Phase 1b Trial Results of Rycal® ARM210 for the Treatment of Ryanodine Receptor 1 Related Myopathies. Retrieved January 30, 2024, from https://www.globenewswire.com/news-release/2024/01/29/2818472/0/en/ARMGO-Pharma-Publishes-Positive-Phase-1b-Trial-Results-of-Rycal-ARM210-for-the-Treatment-of-Ryanodine-Receptor-1-Related-Myopathies.html[3] Inhibikase Therapeutics Announces Publication Highlighting Results from its Phase 1 Studies with Risvodetinib. Retrieved January 30, 2024, from https://www.globenewswire.com/news-release/2024/01/29/2818972/0/en/Inhibikase-Therapeutics-Announces-Publication-Highlighting-Results-from-its-Phase-1-Studies-with-Risvodetinib.html[4] Kiromic BioPharma Reports Favorable Early Efficacy Results from First Patient in Deltacel-01 Phase 1 Clinical Trial in Non-Small Cell Lung Cancer. Retrieved January 30, 2024, from https://www.businesswire.com/news/home/20240129301996/en/[5] First Patient Enrolled in Rise Therapeutics' Rheumatoid Arthritis Clinical Trial. Retrieved January 30, 2024, from https://www.prnewswire.com/news-releases/first-patient-enrolled-in-rise-therapeutics-rheumatoid-arthritis-clinical-trial-302045960.html[5] First Patient Enrolled in Rise Therapeutics' Rheumatoid Arthritis Clinical Trial. Retrieved January 30, 2024, from https://www.prnewswire.com/news-releases/first-patient-enrolled-in-rise-therapeutics-rheumatoid-arthritis-clinical-trial-302045960.html[6] EILEAN THERAPEUTICS COMPLETES SINGLE DOSE STUDIES AND INITIATES MULTIPLE DOSING OF HEALTHY VOLUNTEERS WITH LOMONITINIB, A SELECTIVE PAN-FLT3/IRAK4 INHIBITOR. Retrieved January 30, 2024, from https://www.prnewswire.com/news-releases/eilean-therapeutics-completes-single-dose-studies-and-initiates-multiple-dosing-of-healthy-volunteers-with-lomonitinib-a-selective-pan-flt3irak4-inhibitor-302046981.html[7] First Patient Dosed with LIXTE’s LB-100 and GSK’s Immunotherapy Dostarlimab-gxly in Ovarian Clear Cell Carcinoma Trial. Retrieved January 30, 2024, from https://ir.lixte.com/news-events/press-releases/detail/101/first-patient-dosed-with-lixtes-lb-100-and-gsks-immunotherapy-dostarlimab-gxly-in-ovarian-clear-cell-carcinoma-trial[8] Uvax Bio Announces Dosing of First Participant in Phase 1 Clinical Trial Evaluating Two Vaccines to Prevent HIV-1 Infection. Retrieved January 30, 2024, from https://www.businesswire.com/news/home/20240129742089/en[9] EicOsis Initiates Phase 1b Clinical Trial of EC5026. Retrieved January 30, 2024, from https://www.prnewswire.com/news-releases/eicosis-initiates-phase-1b-clinical-trial-of-ec5026-302047230.html[10] KURA ONCOLOGY REPORTS POSITIVE PRELIMINARY ZIFTOMENIB COMBINATION DATA IN ACUTE MYELOID LEUKEMIA. Retrieved January 31, 2024, from https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-reports-positive-preliminary-ziftomenib[11] Intellia Therapeutics Announces Publication of Positive Interim Phase 1 Data for NTLA-2002 in Patients with Hereditary Angioedema in the New England Journal of Medicine. Retrieved January 31, 2024, from https://www.globenewswire.com/news-release/2024/01/31/2821597/0/en/Intellia-Therapeutics-Announces-Publication-of-Positive-Interim-Phase-1-Data-for-NTLA-2002-in-Patients-with-Hereditary-Angioedema-in-the-New-England-Journal-of-Medicine.html[12] 23andMe Announces FDA Clearance of IND Application for its Dual Mechanism Antibody, 23ME-01473, Targeting ULBP6. Retrieved January 31, 2024, from https://www.globenewswire.com/news-release/2024/01/31/2820995/0/en/23andMe-Announces-FDA-Clearance-of-IND-Application-for-its-Dual-Mechanism-Antibody-23ME-01473-Targeting-ULBP6.html[13] Jaguar Gene Therapy Announces FDA Clearance of IND to Study JAG201 in a Genetic Form of Autism Spectrum Disorder and Phelan-McDermid Syndrome. Retrieved January 31, 2024, from https://www.businesswire.com/news/home/20240131087815/en[14] Vanda Pharmaceuticals Receives FDA Approval to Proceed with Investigational New Drug VTR-297 a Topical Antifungal Candidate for the Treatment of Onychomycosis. Retrieved January 31, 2024, from https://www.prnewswire.com/news-releases/vanda-pharmaceuticals-receives-fda-approval-to-proceed-with-investigational-new-drug-vtr-297-a-topical-antifungal-candidate-for-the-treatment-of-onychomycosis-302049362.html[15] NeuroBo Pharmaceuticals Announces FDA Clearance of IND for a Phase 1 Clinical Trial of DA-1726 for the Treatment of Obesity. Retrieved January 31, 2024, from https://www.prnewswire.com/news-releases/neurobo-pharmaceuticals-announces-fda-clearance-of-ind-for-a-phase-1-clinical-trial-of-da-1726-for-the-treatment-of-obesity-302050383.html免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

2024年1月30日，Ascidian Therapeutics宣布其在研RNA外显子编辑疗法ACDN-01的IND申请已经获得FDA许可，并被授予快速通道资格。ACDN-01是首个获FDA许可进入临床试验的RNA外显子编辑疗法，也是首款专门针对Stargardt病遗传起源的临床期治疗方法。Stargardt病是一种罕见的、原发于视网膜上皮层的常染色体隐性遗传病，患者通常会在儿童或青年时期病发且最终导致失明。研究发现，与Stargardt病发相关的是一种ABCA4基因，该基因含有很长的序列，其突变超过900种，而且不同突变将导致不同程度的蛋白质表达，从而影响疾病的严重程度。这一系列因素使得ABCA4突变相关疾病无法使用常规基因替换或单碱基编辑治疗。截至目前，针对Stargardt病尚无有效的治疗手段。ACDN-01是一种在体内编辑RNA外显子的RNA编辑疗法，与其它只修改一个RNA碱基的RNA编辑器不同，ACDN-01的独特之处在于能够重新书写RNA序列，将导致疾病的RNA序列替换为功能正常的RNA序列，具有使用一种疗法，治疗多种基因突变导致的Stargardt病的潜力。根据新闻稿，Ascidian Therapeutics预计在2024年上半年开始招募参与ACDN-01针对Stargardt病及其他ABCA4相关视网膜病变的I/II期临床试验的患者。Ascidian在研管线来源：Ascidian Therapeutics官网目前，Ascidian已在视网膜、神经和基因疾病等广阔领域中开发产品线，试图解决现有技术无法治愈的重大疾病。那么RNA编辑与DNA编辑相比有什么异同？其发展现状如何？RNA编辑：安全性更高、想象空间更大RNA编辑（RNA editing）是指在RNA水平上发生的碱基增加、删除和替换，使核苷酸序列与基因组DNA序列不同从而引起遗传信息的改变，是一种遗传物质的间接性、高特异性的修复机制。与备受关注的CRISPR-Cas9基因编辑系统不同，RNA编辑只是改变mRNA，不会对基因组造成永久性的改变，因此安全性高、可控性强。而且RNA编辑主要发生在细胞质，不需要穿过细胞核膜，因此对递送的要求低。基于以上优势，RNA编辑在临床应用上有着巨大的想象空间。事实上，RNA编辑并不是一个新概念。早在上世纪80年代，RNA编辑的生物学现象就被发现。1995年，研究人员发现反义寡核苷酸可以募集腺苷脱氨酶（ADARs）到互补RNA链上进行碱基编辑。ADARs的作用机制是与RNA结合后，通过使腺苷（A）脱氨基转变为肌苷（I）来改变RNA分子序列，肌苷I不是典型的RNA碱基，它与鸟苷（G）之间的结构相似性使它会被细胞的翻译机制读取为鸟苷，从而实现A-I-G的转换。当年《PNAS》杂志发表了这项研究，“治疗性RNA编辑”的说法被提出。经过多年的发展，RNA编辑目前主要分为两大技术路线：内源性编辑和外源性编辑。内源性编辑是指通过指导RNA（guide RNA）招募人体内源性的具有催化编辑能力的ADARs或载脂蛋白B mRNA编辑酶（APOBEC）来实现RNA编辑；外源性编辑是指Crispr系统介导的编辑。Cas酶与不同功能的ADARs组成融合蛋白，再通过guide RNA引导，进而帮助ADARs更精准地与特定RNA序列相结合，减少RNA编辑的脱靶效应。两种技术路径各有优劣。RNA编辑的发展现状鉴于RNA编辑广阔的临床应用前景和安全性，这一领域正在吸引海内外药企的关注，不乏罗氏、礼来、GSK等MNC。我们选取海内外进度靠前的药企来具体了解。Wave Life SciencesWave Life Sciences（Wave公司）是一家临床阶段基因药物公司，建立了PRISM技术平台，可实现三种RNA靶向方式：沉默、剪接和编辑，用来开发靶向基因缺陷的寡核苷酸以减少疾病相关蛋白的表达或将功能异常的突变蛋白转化为功能性蛋白。去年12月，Wave公司的在研RNA编辑候选疗法WVE-006在I期临床试验RestorAATion中开始给健康志愿者给药。这是一款潜在FIC的GalNAc共轭RNA编辑寡核苷酸，设计用于纠正SERPINA1 Z等位基因编码mRNA中的单个碱基突变，从而使具备功能的野生型α-1抗胰蛋白酶（AAT）得以恢复和循环，以治疗与α-1抗蛋白酶缺乏症（AATD）相关的肺部或肝脏疾病。2023年12月，Wave与GSK达成战略合作，利用Wave的多模式RNA平台推进RNA药物，包括WVE-006。通过此次合作，Wave获得了1.7亿美元的预付款与研究经费。此外，对于WVE-006，Wave有资格获得高达2.25亿美元的开发和上市里程碑等款项。Shape TherapeuticsShape Therapeutics公司使用其RNA-Fix技术，利用腺苷脱氨酶作用于RNA，进行RNA编辑。此外，Shape还可以使用其RNA-Skip技术，解决突变导致的终止密码子提前问题，恢复全长蛋白的产生。2021年8月，Shape公司和罗氏达成协议，研发RNA编辑疗法，用于治疗多种疾病，包括阿尔茨海默氏症和帕金森氏症。2023年11月，Shape公司与罗氏的合作进一步扩大，双方正在进行的项目中增加了一个新的靶点。ProQR TherapeuticsProQR Therapeutics作为一家RNA编辑公司，其专有的Axiomer平台技术能够以高度靶向和特异的方式编辑RNA中的单核苷酸。该技术利用寡核苷酸编辑（EONs）招募人体内源ADARs，从而实现RNA精准编辑。2021年9月，ProQR宣布与礼来达成全球许可和研究合作，致力于发现、开发和商业化治疗肝脏和神经系统遗传性疾病的潜在新药。两家公司将利用ProQR专有的Axiomer RNA编辑平台，推动新靶点药物的临床开发和商业化。2022年12月，双方扩大了基于该项技术的合作，目前协议总里程碑高达37.5亿美元。聚焦国内，目前博雅辑因、辉大基因、本导基因等在RNA编辑领域进展较快。博雅辑因博雅辑因是一家专注于基因编辑技术转化、处于临床阶段的生物医药企业，致力于针对未被满足的临床需求开发变革型疗法。公司的LEAPER平台利用内源性ADARs对RNA进行程序化编辑。辉大基因辉大基因专注于基因编辑技术和基因治疗药物开发，公司的HG202是一项全新的RNA编辑疗法，依托辉大基因的HG-PRECISE技术平台，将CRISPR/Cas13 RNA编辑器搭载于单个腺相关病毒地送到视网膜，特异性地敲低VEGF-A mRNA表达水平，以治疗已接受过现有抗VEGF疗法有效或耐药的新生血管性（湿性）年龄相关性黄斑变性（nAMD）患者。目前，HG202临床试验已完成首例患者给药。HG204是辉大基因自主开发的另一款RNA编辑疗法。由单个腺相关病毒（AAV）载体递送新型高保真RNA编辑器hfCas13Y及靶向MECP2基因的向导RNA，用于治疗一种罕见且致命的儿童神经发育障碍疾病——甲基化CpG结合蛋白-2（MeCP2）重复综合征（MDS）。临床前研究显示，HG204可在小鼠和猴的脑组织中稳定持续表达，在人源化MDS小鼠模型中可显著降低MeCP2 mRNA和蛋白表达水平，并逆转其疾病特征。本导基因本导基因拥有国际领先的创新型技术平台：VLP mRNA递送与基因编辑平台（BDmRNA），基于此技术平台，公司的BD111（治疗病毒性角膜炎）已完成3例IIT人体临床试验，是目前全球唯一慢病毒递送Cas9 mRNA技术。本导基因还在通过AI辅助设计实现类病毒体VLP的靶向化递送，在提高基因编辑安全性和有效性的同时，扩大适应症，降低基因编辑治疗的成本。目前，RNA编辑技术尚未成熟，疗法开发仍然处于临床初期研究阶段，但是业界已经看到RNA编辑的潜力。与DNA编辑造成的永久化变化不同，RNA编辑因为其可逆性的特点，在临床应用上有着巨大的想象空间，其在常见病领域的应用非常值得期待。我们也期待在资本的助力下，这一前沿技术能早日迎来自己的高光时刻。参考来源Ascidian Therapeutics announces first-ever IND for an RNA exon editor as FDA approves Trial Plan and Fast Tracks ACDN-01 in Stargardt Disease and other ABCA4 retinopathies.https://www.prnewswire.com/news-releases/ascidian-therapeutics-announces-first-ever-ind-for-an-rna-exon-editor-as-fda-approves-trial-plan-and-fast-tracks-acdn-01-in-stargardt-disease-and-other-abca4-retinopathies-302046287.html.Wave Life Sciences Announces Submission of First Clinical Trial Application for WVE-006, the First-ever RNA Editing Clinical Candidate, and Plans for Upcoming Virtual “R&D Day”.ProQR Announces Axiomer® RNA Editing Licensing and Research Collaboration with Lilly. Retrieved September 9, 2021, from https://www.globenewswire.com/news-release/2021/09/08/2293799/33039/en/ProQR-Announces-Axiomer-RNA-Editing-Licensing-and-Research-Collaboration-with-Lilly.html.https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-fda-clearance-investigational-0.