PDE6B

SparingVision Reaches Final Dose Escalation Step in PRODYGY Trial with SPVN06 for retinitis pigmentosa Positive recommendation received from the Data Safety Monitoring Board (DSMB) enabling progression to highest dose of Part 1 of the PRODYGY trialFavorable safety and tolerability profiles observed with first two SPVN06 doses across six patients (three patients per cohort)Exploration of SPVN06 in geographic atrophy to begin in 2024 Paris, 24 January 2024 – SparingVision (“the Company”), a clinical-stage genomic medicine company transforming the treatment of retinal disease, today announces a key advancement in its Phase I/II clinical trial (PRODYGY, NCT05748873) for SPVN06, the Company’s lead gene-agnostic investigational gene therapy for the treatment of retinitis pigmentosa (RP). The trial has now progressed to the final dose cohort of the dose-escalation phase (Part 1). This positive recommendation from the Data Safety Monitoring Board (DSMB) represents a further step towards the commencement of the controlled part of the study (Part 2) anticipated to start in Q2 2024, in line with study development timelines. SPVN06 is a breakthrough gene therapy approach aimed at stopping or slowing disease progression in patients affected by rod-cone dystrophy, (RCD), regardless of their genetic background. SparingVision is initially focusing on mid-stage RP, one of the leading inherited causes of blindness globally. This progress of the PRODYGY trial to the third cohort at the highest dose of SPVN06 follows an earlier positive recommendation from the DSMB to dose the second cohort at the medium dose in August 2023. The two positive recommendations received to date from the DSMB were based on the favorable safety and tolerability profiles observed in patients treated with the lower (first cohort) and medium (second cohort) doses of SPVN06. After completion of the third and final cohort in Part 1, the Company plans to advance the PRODYGY trial to Part 2, a three-arm controlled, double-masked, randomized extension phase investigating two doses of SPVN06 and one untreated arm, with additional clinical sites opening in the United States. The primary endpoint of the PRODYGY Phase I/II trial is expected to be reached in the second half of 2025, twelve months after the last patient in Part 2 is dosed. Stéphane Boissel, President and Chief Executive Officer of SparingVision, said: “We are encouraged by the strong safety and tolerability profile of SPVN06 demonstrated so far. This milestone not only allows us to progress to the highest dose and, pending further DSMB positive recommendation, start Part 2 in Q2 2024; it also gives us the added confidence to expand the evaluation of SPVN06 to geographic atrophy (GA), another significant blinding condition. We are excited about the future as we continue to advance our portfolio of pioneering genomic medicines to save sight.” With the encouraging safety data gathered in PRODYGY so far and supported by a body of evidence and KOL insights, SparingVision believes in the strong potential of SPVN06 in other retinal diseases for which cone preservation is the landmark for stopping disease progression. The Company intends to explore the benefits of its gene therapy for the treatment of geographic atrophy (GA), with a view to potentially initiating Investigational New Drug (IND)-enabling studies for GA in 2024. PRODYGY trial PRODYGY (Promising ROd-cone DYstrophy Gene therapY) is a multicentric Phase I/II trial to assess the safety, tolerability as well as preliminary efficacy and quality-of-life following a single subretinal injection of SPVN06 in the worst-seeing eye of adult patients with RCD due to a mutation in the RHO, PDE6A, or PDE6B gene. The study aims to recruit a total of 33 patients in two parts: Part 1: open-label, dose-escalation phase including three cohorts of three patients with severe advanced RCD, to determine two recommended best-tolerated doses for Part Two.Part 2: controlled, double-masked, randomized extension phase including 24 patients with intermediate advanced RP, divided into three cohorts: six untreated subjects and 18 patients receiving one of the two recommended doses determined in Part One. Further information on the trial can be found on www.ClinicalTrials.gov (CT identifier: NCT05748873). **ENDS** Contacts: SparingVisionStéphane BoisselPresident and CEONathalie TrepoInvestor Relations nathalie.trepo@sparingvision.comICR ConsiliumAmber Fennell, Namrata Taak, Davide Salvi+44 (0)20 3709 5700sparingvision@consilium-comms.com NOTES TO EDITORS: About SparingVision SparingVision is a global ophthalmology leader bringing new hope to millions affected by retinal diseases, for which there are currently no viable treatments. The Company has assembled a suite of cutting-edge technologies from gene therapy to CRISPR, enabling it to deploy the right technology to the right disease and ensure the delivery of breakthrough treatments to millions of patients. Both of its products, SPVN06 and SPVN20 go beyond single gene correction therapies to deliver new gene-agnostic treatments for Retinitis Pigmentosa, a group of inherited retinal diseases which are the leading cause of blindness globally. The Company also has a strategic collaboration with Intellia Therapeutics (NASDAQ:NTLA) to develop novel genome editing-based treatments for ocular disease utilizing CRISPR-Cas9 technology. SparingVision is a spin-off from the Paris Vision Institute and backed by high-quality international investors including 4BIO Capital, Advent France Biotechnology, Bpifrance, Foundation Fighting Blindness (US), Fondation Voir & Entendre, Intellia Therapeutics, UPMC Enterprises, Jeito Capital and Ysios Capital.Visit www.sparingvision.com for more and follow us on LinkedIn and X (formerly Twitter) @SparingVision About SPVN06 SPVN06 is a proprietary, mutation-agnostic, AAV gene therapy approach comprised of one neurotrophic factor (Rod derived Cone Viability Factor, RdCVF) and one enzyme reducing oxidative stress (Rod derived Cone Viability Factor Long form, RdCVFL). Acting synergistically, RdCVF and RdCVFL aim at slowing or stopping the degeneration of cone photoreceptors, which inevitably leads to blindness in patients with rod-cone dystrophies (RCD). SparingVision’s primary disease targets are retinitis pigmentosa (RP), one of the most common inherited retinal diseases that affects an estimated two million patients worldwide and dry Age-related Macular Degeneration (AMD). There is currently no treatment approved to treat RP patients independently of their genetic background. This approach is potentially applicable to many more diseases, where the loss of rods is known to be an early signal of the disease. SPVN06 is the result of decades of world-leading ophthalmology research by SparingVision founders José-Alain Sahel and Thierry Léveillard at the Paris Vision Institute

摘要亨廷顿舞蹈症是一种罕见的遗传性疾病，发病率在万分之一和十万分之一之间。在患者体内，4号染色体短臂上一个名为Huntington（Htt）的基因出现遏变异，携带大量的CAG三碱基重复序列，从而破坏了Htt蛋白的正常结构和功能，导致神经细胞的大量死亡，严重影响了患者的大脑功能，尤其是运动控制机能。近年来，旨在靶向降解突变Htt蛋白、或利用反义寡核苷酸技术降解突变Htt mRNA的药物开发路径成为热点，但至今尚未取得临床突破。与此同时，利用基因编辑技术修改乃至复原Htt基因，也在多种动物模型中得到了测试，有待进一步人体实验验证。本期报告聚焦于近期中国科学家在亨廷顿舞蹈症猪模型上进行基因编辑治疗的研究，并探讨这条技术路线的价值和困难。亨廷顿舞蹈症在全球范围内的发病率在十万分之一到万分之一之间。之所以被叫作“亨廷顿舞蹈症”，是因为美国医生乔治·亨廷顿（George Huntington）在1872年首先对这一类病患进行了详细的追踪和记录。他注意到在某些家族中，代代都会有人患上一种特殊的疾病，往往表现为在30-50岁之间出现记忆和认知功能的衰退、抑郁和妄想等精神问题，当然更为突出的是运动机能的下降。患者会出现眼球、面部和肢体的不自觉震颤、抖动和摇晃，可逐渐发展到全身无规律地摆动，状似不由自主地舞蹈，因此得名。患者往往会在出现症状后的10-15年内死亡，死因包括跌倒受伤、长期卧床导致的并发症和自杀等。在20世纪80-90年代，研究者们认识到亨廷顿舞蹈症是一种常染色体显性遗传病，基因变异出现在4号体短臂上一个名为Huntington的基因内部。这个简称为Htt的基因对于动物和人类的正常发育是必须的，也对大脑神经细胞的正常活动有贡献，但具体作用方式并不十分清楚。在这个基因内部存在一连串由CAG三个碱基形成的重复序列（CAGCAGCAG...），在制造相对应的蛋白质分子的时候，CAG三联碱基对应的是一个特定的氨基酸——谷氨酰胺（Glutamine，简称Q）。在大多数健康人中，CAG重复序列，或者说氨基酸Q的重复次数，在几个到二三十个之间不等。而如果Q重复次数超过40，Htt蛋白质的分子结构和功能就会受到剧烈的干扰，它们能在神经细胞内彼此交联形成聚集，破坏细胞的正常功能，最终导致神经细胞死亡和大脑功能障碍。也有研究发现，Q的重复数量越大，患者发病时间往往越早，疾病症状也越严重。很显然，如果父母双方携带了含有超量CAG重复序列的Htt基因（又被称为mHtt，mutant Htt），就有可能把这种基因变异传递给子女，从而让疾病在家族内代代相传。很容易联想到，亨廷顿舞蹈症的发病机理，和更为常见的神经退行性疾病，如阿尔茨海默症、帕金森氏症有相似之处。后两者的发病过程中也包括异常蛋白质分子的出现和形成聚集，如阿尔茨海默症患者脑中由Abeta蛋白形成的淀粉样沉淀，和由超磷酸化tau分子形成的神经纤维缠结，以及帕金森氏症患者大脑中alpha-突触核蛋白（alpha-synuclein）形成的沉淀。和病因更加复杂难解的后两种疾病相比，亨廷顿舞蹈症的病因是非常单纯和专一的：就是Htt基因内部CAG碱基重复数量的增加。因此有很多人认为在最终征服神经退行性疾病的道路上，亨廷顿舞蹈症会是率先被攻克的“低垂的果实”。但事与愿违的是，至今还没有诞生任何一个能从根本上延缓、逆转和预防亨廷顿舞蹈症发病的方法。在临床实践中，医生们只能根据亨廷顿舞蹈症患者的具体症状给予对症治疗，例如用抗抑郁药缓解患者的情绪问题，用安眠药对抗失眠问题，如果患者出现肌肉痉挛导致的吞咽困难，则需要直接在胃部造瘘直接送入食物等。相比之下，倒是在更为复杂的阿尔茨海默症和帕金森氏症当中，多种有效的药物和医疗器械被陆续发明出来，例如2023年刚刚获批的阿尔茨海默症药物Leqembi。那么，究竟要如何彻底解决亨廷顿舞蹈症的问题呢？其实从逻辑上说，既然我们已经知道这种疾病的直接病因，就是含有太多谷氨酰胺重复的mHtt蛋白（或者说含有太多CAG重复的mHtt基因），那么如果能够在患者大脑中降低这种蛋白的产量（或者降低这个基因的活动），应该就能起作用。最直接的思路是设计药物降解破坏mHtt蛋白。这一点实现起来并不容易，因为传统小分子药物的设计要么是结合一个酶分子的活性部位并阻止其工作，要么是结合在蛋白质分子的某个接触界面阻止其和其他蛋白质结合。但mHtt蛋白本身是不是有酶活性、有什么样的酶活性、和什么蛋白质的结合对疾病最为关键，本身都还是没有完全搞清楚的问题，因此无法有的放矢地设计小分子药物。而单抗类药物固然能专一性地结合目标蛋白，但单抗药物又无法轻松进入细胞内部识别mHtt。在过去几年，研究者们开发了几种全新类型的小分子药物来实现这个目的。这些分子的工作原理大致是这样的：它们可以一头牢牢结合Htt蛋白，另一头则结合能够导致蛋白降解的泛素连接酶或自噬小体，从而把致病蛋白质拖入细胞内的废物处理厂中，破碎处理掉。这类思路广义上都属于近年来大红大紫的蛋白质降解药物（Protein Degraders），确实被很多人寄予厚望。当然，这个思路虽然已经被证明能够有效降解mHtt，但目前还没有进入真正的临床试验阶段。在此之外，另一个相辅相成的思路是降解生产mHtt蛋白的信使RNA（mRNA, messenger RNA）。我们应该都知道生物学的中心法则：DNA携带遗传信息，DNA根据自身序列制造mRNA，而mRNA则根据自身序列制造蛋白质。因此，如果把mHtt基因所对应的信使RNA分子破坏掉，也能阻止致病Htt蛋白的生产。例如，由美国Ionis公司开发的反义寡核苷酸(ASO，antisense oligonucleotides)药物Tominersen，在脑中可以和mHtt基因的mRNA分子配对结合，导致后者的降解。但遗憾的是，在2021年，这款药物的三期临床试验被叫停，原因可能是在亨廷顿舞蹈症患者中并未看到疾病症状的改善。当然，这条技术路线仍然并未被宣判死刑，在2022年，Tominersen的开发者们又启动了一项全新的临床研究，试图在年龄和症状都较轻的患者中再次尝试降解mHtt蛋白是否可以治疗疾病。另一家采用类似技术路线的公司，Wave Life Sciences，也在临床研究中积极推进它们的反义寡核苷酸产品。如果把上述两种思路看成是扬汤止沸——在mHtt蛋白出现后再想办法破坏它，那么基因疗法则有可能起到釜底抽薪的作用——直接修改mHtt基因，彻底破坏其制造蛋白质的能力，或者干脆把它内部的CAG重复数量降低到健康人水平。前者在技术上较为容易实现。过去十年来，以CRISPR/cas9技术为代表的基因编辑技术在定点破坏基因序列已经展示了惊人的实力。在特定向导RNA（gRNA, guide RNA）的引导下，cas9蛋白质可以被定位到生物基因组DNA的特定位置，并且切断DNA双链。而因为细胞内并没有默认正确的序列可供修复时参照，在DNA双链重新愈合修复的过程中，往往会随机增加或者丢失几个碱基。由于DNA编码的逻辑是三个碱基分子的组合对应一个氨基酸，这种随机改变将会大概率彻底破坏掉一个基因编码蛋白质的功能。举例来说，2021年首次进行体内基因编辑临床试验的Intellia公司，就是利用CRISPR/cas9技术定点破坏了患者体内出现基因变异的转甲状腺素基因（TTR, Transthyretin），从而治疗由这种基因变异导致的罕见遗传病——遗传性转甲状腺素淀粉样变性。基于类似的逻辑，2017年，研究者们也在亨廷顿舞蹈症的小鼠模型上做了类似的尝试。这种小鼠的Htt基因内部被人为插入了一段140个CAG重复序列，用于模拟严重的亨廷顿舞蹈症患者。这些小鼠也确实出现了明显的mHtt蛋白表达、Htt蛋白的大规模聚集、以及运动机能的障碍。研究者们证明，用改造过的腺相关病毒（AAV, adeno-associated virus）作为载体，将CRISPR/cas9系统投送到小鼠脑中，在140个CAG重复序列的两侧各切一刀，制造两个DNA断口。两端DNA断口重新愈合之后，不仅会丢掉中间的140个CAG重复，还往往会顺带破坏掉整个mHtt基因的功能。研究者们也确实证明，这个办法不光能够有效的去除mHtt蛋白，还能显著改善小鼠的运动能力。但上述研究一个明显的遗憾是，亨廷顿舞蹈症的小鼠模型固然在遗传学上和人类患者相似，而且也能出现运动机能障碍，但却和人类患者有一个相当根本性的区别：这些小鼠的大脑神经细胞并不会因此而死亡。换句话说，亨廷顿舞蹈症小鼠模型展示的，可能是由大量mHtt蛋白表达和堆积导致的神经毒性疾病，而不是人类那样的由大量神经细胞死亡导致的神经退行性疾病。为了解决这个问题，同时也为了在体型更接近人类的动物中模拟亨廷顿舞蹈症，研究者们在2018年开发出了亨廷顿舞蹈症的猪模型。其构建方法和小鼠模型类似，也是在Htt基因中插入了一段由150个CAG组成的重复序列。但和小鼠不同的是，这些转基因猪除了呈现出了mHtt蛋白的累积和聚集，行为能力和整体健康的衰退之外，还表现出了明显的和人类患者接近的神经退行症状：在不同脑区中都观察到了神经细胞的死亡和大脑结构的变化。显然，不管是用于研究亨廷顿舞蹈症的致病机理，还是测试亨廷顿舞蹈症的候选药物，这种猪模型都比小鼠模型要更有价值。在2023年初，同一群研究者们又进一步把上述两项研究进行了综合：它们试图在亨廷顿舞蹈症猪模型中，验证基因编辑是否可以治疗疾病。具体来说，基本的试验设计是这样的：我们已知，如果猪的mHtt基因内部携带150个CAG重复序列，这些猪会表现出类似人类亨廷顿舞蹈症的神经退行性症状。于是，在这些猪的脑内，研究者们注射了两个AAV病毒载体，一个装载了cas9蛋白，一个则装载了和上述小鼠实验一样的两个向导RNA序列，分别指向CAG重复序列的两端。这两个病毒载体进入大脑后，能够将负责切割DNA的cas9和负责定位的向导RNA导入同一细胞。这样一来，在这些细胞内部，CRISPR/cas9系统就能够制造两个断口，将多余的CAG重复序列切除，并且在mHtt基因内部制造微小的随机序列增加或减少，从而彻底破坏mHtt基因的功能。但值得一提的是，除了上述常规设计之外，研究者们这一次还增加了一个新的技术变量。在投送基因编辑工具的同时，它们还把一段正常的、仅含有20个CAG重复的Htt基因序列投送到了猪的大脑中。为什么这么做呢？这是因为，在CRISPR/cas9工具切断DNA之后，新出现的DNA断口有两种常见的修复模式。一种模式就是刚刚我们描述的较为粗糙和随机的模式，学名叫做“非同源末端连接”（NHEJ, non-homologous end joining），大致可以理解成两个DNA断口被强行拼接在一起，因为细胞也不知道正确的拼法应该是什么，所以会出现各种随机的微小错误，从而破坏基因的功能。而另一种模式则是，如果恰好在断口附近存在一段和断裂的DNA序列高度一致的DNA片段，那么细胞就会倾向于选择以这段DNA片段为模板，把断口位置修复得和模板完全一致，这种模式学名叫做“同源重组修复”（HDR, homology directed repair）。基于这个原因，把一段仅含有20个CAG重复的Htt基因序列投送到细胞内，当CRISPR/cas9工具在Htt基因内部制造两个断口之后，就会产生两个可能的结果：一个是，细胞会利用这段含有20个CAG重复的序列进行修复，把mHtt基因替换成正常Htt基因，其中仅含有20个CAG重复，不会引起疾病；另一个则和刚刚描述的没有区别，细胞忽略了这段同源序列的存在，继续进行非同源末端链接，直接破坏mHtt基因的功能。单纯从治疗疾病的角度，两者可能没有本质的区别。因为不管是把mHtt基因修复成正常的样子，还是破坏掉mHtt基因的功能，都能够减少细胞内的mHtt蛋白，消除亨廷顿舞蹈症的直接病因，改善疾病的症状。事实上在这项研究中，研究者们也确实证明了大脑中mHtt蛋白的含量被有效降低了超过50%，猪的疾病症状也得到了非常显著的改善。而且还必须要说明的是，同样是修复DNA断口，同源重组修复的效率要远低于非同源末端连接——这本身到不奇怪，毕竟前者多出了一个寻找修复模板进行替换的过程。具体到这项研究中，研究者们也发现，在对猪进行基因编辑操作的时候，在那些成功实现了基因编辑的细胞中，大约只有15-20%的细胞完成了同源重组修复，获得了正常的Htt基因；而其余细胞中仍然进行的是非同源末端连接，mHtt基因被彻底破坏了。“ 即便如此，这种修复仍然是值得探索的一种技术方案。”首先，尽管人们已经知道，Htt基因在成年动物体内并不重要，即便缺失也不影响动物的正常生活，但在成年和老年人中我们很难说它一点功能都没有。因此对于一个出了问题的mHtt基因，能够把它修复成正常的样子，让它执行某种未知的、但可能并非无关紧要的功能，总比不分青红皂白就把它彻底破坏了好。其次，就算亨廷顿舞蹈症的治疗不需要这么精致，还有很多人类疾病，特别是遗传疾病，背后是某个基因特定位置的变异和某个基因具体功能的变化，需要的是精确修复而不是粗暴破坏。举个例子来说，由Pde6b基因变异导致的视网膜色素变性患者，需要的治疗方案就是对Pde6b基因的序列进行精确修复。在这个时候，摸索如何实现更精确的同源重组修复，同时进一步提高其体内效率，就是非常重要的。因此，这项在亨廷顿舞蹈症猪模型中进行的探索，也能帮助我们进一步理解在大型动物体内进行精确基因修复的可行性、难度和未来优化方向。同时非常值得提出的是，研究者们还尝试了在新生小猪中利用静脉注射而非脑内直接注射病毒的方法实现基因编辑和修复，同样证明了治疗的有效性。这说明，起码在新生儿阶段，静脉注射病毒已经足以保证基因编辑工具顺利进入大脑并编辑足够数量的细胞，展现出持久的治疗效果（在成年动物体内，因为体型和身体结构原因，也许静脉注射的可行性就大大降低了）。这当然是个好消息，在脑内注射AAV病毒尽管已经是常规技术，但毕竟涉及到在颅骨打洞、颅内注射等一系列手术操作，患者的接受度和术后感染的风险都不容乐观。如果能直接静脉注射治疗脑内疾病，这对医生和患者都是很好的消息。“ 在世界范围内，基因治疗，也包括多种全新基因编辑工具的应用，正在成为生物医药市场新的热点。”人们期待针对人体致病基因开展的治疗，能够像曾经的重组蛋白药物、单克隆抗体药物、RNA疫苗、小核酸药物那样改变很多疾病的治疗模式，制造新的产业机会。近年来也有多款基于AAV病毒载体的基因治疗产品获批上市（例如治疗脊髓性肌萎缩症的药物Zolgensma，治疗遗传性视网膜营养不良的药物Luxturna，治疗芳香族L-氨基酸脱羧酶缺乏症的Upstaza等）。也许久攻不克的神经退行性疾病，包括亨廷顿舞蹈症、阿尔茨海默症和帕金森氏症等，也能从基因治疗的全新进步中，获得新的解决思路。参考文献：[1] Bhattacharyya K. 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Paris, France, September 28, 2023 – Coave Therapeutics (‘Coave’), a genetic medicine company focused on developing life-changing therapies for CNS (Central Nervous System) and eye diseases, announces that CEO Rodolphe Clerval will be presenting to investors and peers at the following Investor and Industry conferences: Chardan’s 7th Annual Genetic Medicines Conference – October 2-3 New York City, NY, USAPresenting on October 2 at 11:30 EDT Cell & Gene Meeting on the Mesa – October 10-12 Carlsbad, CA, USAPresenting on October 10 at 13:15 PDT and on panel “Science Slam: Path To Commercialization In Gene Therapy” at 14:00 PDT Jefferies London Healthcare Conference – November 14-15 London, UKAttending and available for investor meetings In addition, science and data from Coave’s pipeline programs will be presented at the following Scientific, Medical & Regulatory Conferences: EURETINA (European Society of Retina Specialists) Congress – October 5-8 Amsterdam, the NetherlandsOral presentation by Professor G. Le Meur: “Design of a Phase 1/ 2 Trial to Study the Safety and Efficacy of a Unilateral Subretinal Administration of HORA-PDE6B in Patients with Retinitis Pigmentosa (RP) Harbouring Mutations in the PDE6B (Phosphodiesterase 6B) Gene Leading to a Defect in PDE6B Expression.” RD 2023 – the XXth International Symposium on Retinal Degeneration – October 23-28 Torremolinos, Spain ESGCT (European Society of Gene and Cell Therapy) 30th Annual Congress – October 24-27 Brussels, BelgiumOral Presentation by Dr. M.A. Burlot: “Intrastriatal injection of S0112AAV2-GBA1 is an efficient strategy to treat patients suffering from Parkinson’s disease related to GBA1 mutations.” Presentation on 27 October, 08:30-10:00 CEST (ID# OR65)Poster presentation: “Improving AAV vectors via chemical engineering using the AAV-Ligand conjugation platform (ALIGATER™).” (Poster ID# P200)Poster presentation: “Chemically modified AAV (coAAV) vectors from the AAV-Ligand Conjugate (ALIGATER™) platform possess modulated properties after systemic injection versus parental unconjugated capsids.” (Poster ID# P177) *** About Coave Therapeutics At Coave Therapeutics, we are leading the transition of genetic medicine from rare to prevalent conditions, starting with neurodegenerative and eye diseases. The Company’s proprietary Advanced Vectors-Ligand Conjugates (‘ALIGATER’) platform introduces chemical modifications onto AAV capsids or Lipid Nanoparticles (LNPs), overcoming the limitations of current vectors on efficacy, safety, and manufacturability. With low doses and optimized routes of administration, our conjugated vectors have demonstrated markedly improved transduction and biodistribution in the central nervous system and the eye across different species. Our diverse pipeline of novel genetic medicines can potentially transform the lives of people afflicted by rare and prevalent neurodegenerative and ocular diseases – including genetically and non-genetically defined indications. Headquartered in Paris, France, Coave Therapeutics is backed by leading international life sciences investors. For more information about the science, pipeline, and people, please visit https://coavetx.com/ and follow us on LinkedIn. CONTACTS Coave TherapeuticsRodolphe Clerval, CEOcontact@coavetx.com MEDiSTRAVA ConsultingSylvie Berrebi, Leila Adlam, Mark Swallowcoavetx@medistrava.comTel: +44 (0)203 928 6900