A Phase 1/2a, Open-Label, Non-Randomized, Dose-Escalation Study to Evaluate the Safety and Tolerability of GS030 in Subjects With Retinitis Pigmentosa

The objective of this study is to evaluate the safety and tolerability of escalating doses of a gene therapy called GS030-DP (injected study treatment) administered via a single intravitreal injection and repeated light stimulation using a medical device called GS030-MD (stimulating glasses) in subjects with documented diagnosis of non-syndromic Retinitis Pigmentosa

开始日期2018-09-26

申办/合作机构

Gensight Biologics SA

100 项与 GS030 相关的临床结果

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100 项与 GS030 相关的转化医学

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100 项与 GS030 相关的专利（医药）

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项与 GS030 相关的文献（医药）

2023-12-01·Molecular therapy : the journal of the American Society of Gene Therapy

Intravitreal injection of a rationally designed AAV capsid library in non-human primate identifies variants with enhanced retinal transduction and neutralizing antibody evasion

Article

作者: Gupte, Siddhant ; Kellish, Patrick C ; Boye, Sanford L ; Marsic, Damien ; Kondratova, Liudmyla ; Crosson, Sean M ; Hill, Julie ; Zolotukhin, Sergei ; Fajardo, Diego ; Peterson, James J ; Makal, Victoria ; Scalabrino, Miranda L ; Choudhury, Shreyasi ; Strang, Christianne E ; McCullough, K Tyler ; Iyer, Siva ; Gamlin, Paul D ; Boye, Shannon E ; Witherspoon, C Douglas ; Kondratov, Oleksandr

Adeno-associated virus (AAV) continues to be the gold standard vector for therapeutic gene delivery and has proven especially useful for treating ocular disease. Intravitreal injection (IVtI) is a promising delivery route because it increases accessibility of gene therapies to larger patient populations. However, data from clinical and non-human primate (NHP) studies utilizing currently available capsids indicate that anatomical barriers to AAV and pre-existing neutralizing antibodies can restrict gene expression to levels that are "sub-therapeutic" in a substantial proportion of patients. Here, we performed a combination of directed evolution in NHPs of an AAV2-based capsid library with simultaneous mutations across six surface-exposed variable regions and rational design to identify novel capsid variants with improved retinal transduction following IVtI. Following two rounds of screening in NHP, enriched variants were characterized in intravitreally injected mice and NHPs and shown to have increased transduction relative to AAV2. Lead capsid variant, P2-V1, demonstrated an increased ability to evade neutralizing antibodies in human vitreous samples relative to AAV2 and AAV2.7m8. Taken together, this study further contributed to our understanding of the selective pressures associated with retinal transduction via the vitreous and identified promising novel AAV capsid variants for clinical consideration.

2023-09-06·Molecular therapy : the journal of the American Society of Gene Therapy

Combined AAV-mediated gene replacement therapy improves auditory function in a mouse model of human DFNB42 deafness.

Article

作者: Chien, Wade ; Cartagena-Rivera, Alexander X ; Belyantseva, Inna A ; Isgrig, Kevin ; Grati, Mhamed ; Fernandez, Katharine A ; Friedman, Thomas B ; Wang, Hong Jun

Hearing loss is a common disorder affecting nearly 20% of the world's population. Recently, studies have shown that inner ear gene therapy can improve auditory function in several mouse models of hereditary hearing loss. In most of these studies, the underlying mutations affect only a small number of cell types of the inner ear (e.g., sensory hair cells). Here, we applied inner ear gene therapy to the Ildr1^{Gt(D178D03)Wrst} (Ildr1^w-/-) mouse, a model of human DFNB42, non-syndromic autosomal recessive hereditary hearing loss associated with ILDR1 variants. ILDR1 is an integral protein of the tricellular tight junction complex and is expressed by diverse inner ear cell types in the organ of Corti and the cochlear lateral wall. We simultaneously applied two synthetic adeno-associated viruses (AAVs) with different tropism to deliver Ildr1 cDNA to the Ildr1^w-/- mouse inner ear: one targeting the organ of Corti (AAV2.7m8) and the other targeting the cochlear lateral wall (AAV8BP2). We showed that combined AAV2.7m8/AAV8BP2 gene therapy improves cochlear structural integrity and auditory function in Ildr1^w-/- mice.

2023-03-01·Ultrasound in medicine & biology

Evaluation of Non-invasive Optogenetic Stimulation with Transcranial Functional Ultrasound Imaging

Article

作者: Kwon, Nancy ; Pouliopoulos, Antonios N ; Murillo, Maria F ; Konofagou, Elisa E ; Aurup, Christian

Optogenetics employs engineered viruses to genetically modify cells to express specific light-sensitive ion channels. The standard method for gene delivery in the brain involves invasive craniotomies that expose the brain and direct injections of viruses that invariably damage neural tissue along the syringe tract. A recently proposed alternative in which non-invasive optogenetics is performed with focused ultrasound (FUS)-mediated blood-brain barrier (BBB) openings has been found to non-invasively facilitate gene delivery for optogenetics in mice. Although gene delivery can be performed non-invasively, validating successful viral transduction and expression of encoded ion channels in target tissue typically involves similar invasive techniques, such as craniotomies in longitudinal studies and/or postmortem histology. Functional ultrasound imaging (fUSi) is an emerging neuroimaging technique that can be used to transcranially detect changes in cerebral blood volume following introduction of a stimulus. In this study, we implemented a fully non-invasive combined FUS-fUSi technique for performing optogenetics in mice. FUS successfully delivered viruses encoding the red-shifted channelrhodopsin variant ChrimsonR in all treated subjects. fUSi successfully identified stimulus-evoked cerebral blood volume changes preferentially in brain regions expressing the light-sensitive ion channels. Improvements in cell-specific targeting of viral vectors and transcranial ultrasound imaging will make the combined technique a useful tool for neuroscience research in small animals.

项与 GS030 相关的新闻（医药）

2024-06-20

·BioSpace

GenSight Biologics Renegotiates Financial Obligations and Provides Operational Updates

PARIS--(BUSINESS WIRE)-- Regulatory News: GenSight Biologics (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible), a biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today announced the renegotiation of certain financial obligations, securing its financial position and improving short-term flexibility. The Company also provided operational updates. In connection with its two recent successful capital increases in February 2024 and May 2024, the Company initiated discussions with its creditors. As a result of these discussions, the Company and its creditors have renegotiated the terms and conditions of certain financial obligations. “We continue to make progress in optimizing financial management to support our objectives, and we are grateful to our banking partners and creditors for their continued collaboration in our journey,” commented Laurence Rodriguez, Chief Executive Officer of GenSight Biologics. “The renegotiated terms will give GenSight additional operating flexibility as it works on its priorities.” Renegotiation of the terms of state-guaranteed loans The Company and its creditor banks (BNP Paribas, CIC and Bpifrance) (the "Banks"), previously agreed to suspend the payment of the principal, subject to certain conditions. The parties have now agreed to extend the maturity of the loans until December 2024 and to adopt a new payment schedule for the outstanding principal and interest, featuring 6 monthly instalments with gradual amortization (5% of outstanding principal per month over July, August and September 2024, and then 28.3% over October, November and December 2024). Renegotiation of the terms for the convertible bonds with Heights Capital As previously announced, an additional amendment to the price limit set forth in the terms and conditions of the convertible bonds issued on December 28, 2022, to Heights Capital (the "2022 OCA”) was presented to the shareholders at the annual shareholders’ general meeting ("AGM") held on May 29, 2024, and was approved as the 30th resolution of the AGM. This new price limit equals to €0.3272 (the "Price Limit"1). The Company and Heights Capital previously decided to suspend the quarterly amortization payments for the redemption of the 2022 OCAs. In recently concluded discussions, the Company and Heights Capital have agreed that (i) the frozen quarterly amortization payments will be paid in accordance with the additional amortization rights mechanism contained in the terms and conditions of the 2022 OCAs and (ii) the quarterly amortization payment of the 2022 OCAs will resume through the issue of new shares by the Company starting from the amortization payment for June 28, 2024. Ongoing renegotiation of the terms for loan tranche from the European Investment Bank (EIB) As previously announced, the withdrawal of the GS010 (LUMEVOQ®) marketing authorization application in 2023 and the revision of the Company’s manufacturing plans invalidated the conditions for drawing down the €12 million Tranche B of the EIB loan from November 2022. The EIB and the Company have agreed to continue negotiating new drawdown conditions for Tranche B. Working Capital Statement The Company confirms that it has sufficient net working capital to meet its obligations until the second part of the third quarter of 2024. With the potential revenues generated by the resumption of AAC program, assuming the manufacture of the drug product batch for the AAC program is completed as planned, the Company anticipates that it would have sufficient net working capital to meet its obligations until the second quarter of 2025. Operational Updates The Company remains on track to resume the early access program (AAC) for GS010 (LUMEVOQ®) in France in Q3 2024. The blending of the two drug substance batches produced in 2023 is on track, and the Company has been in contact with the French medicines safety agency (ANSM) and Paris’ Quinze-Vingts Hospital (the reference medical center where initial treatments for the AAC will take place) to secure operational readiness as soon as product becomes available in Q3 2024. “The team is very much focused on having everything in place, so that patients, who we know have been waiting to be treated, can have access to the drug as soon as possible,” said Magali Taiel, Chief Medical Officer of GenSight Biologics. “Their urgency is ours.” As the company prepares for the release of five-year data from the REFLECT Phase III study of LUMEVOQ®, it has also conducted feasibility studies for the upcoming global RECOVER Phase III study, which is expected to start enrolling patients in H2 2025. Work continues on finalizing the protocol to address all comments received from regulatory authorities. Follow-up of GS030 (an optogenetic treatment candidate for Retinitis Pigmentosa) patients treated in the PIONEER Phase I/II trial is ongoing, with intermediate results from PIONEER expected in 2025. In parallel, the Company is advancing on a number of discussions with potential partners on strategic opportunities, including a possible merger, acquisition or licensing deal, assessed as one of the relevant options to move forward. About GenSight Biologics GenSight Biologics S.A. is a clinical-stage biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders. GenSight Biologics’ pipeline leverages two core technology platforms, the Mitochondrial Targeting Sequence (MTS) and optogenetics, to help preserve or restore vision in patients suffering from blinding retinal diseases. Using its gene therapy-based approach, GenSight Biologics’ product candidates are designed to be administered in a single treatment to each eye by intravitreal injection to offer patients a sustainable functional visual recovery. GenSight Biologics’ lead product candidate, LUMEVOQ® (GS010; lenadogene nolparvovec), an investigational compound that has not been registered in any country at this stage, was developed for the treatment of Leber Hereditary Optic Neuropathy (LHON), a rare mitochondrial disease affecting primarily teens and young adults that leads to irreversible blindness. The company is also developing an optogenetics product candidate, GS030, for the treatment of rare inherited diseases, such as Retinitis Pigmentosa, that cause degeneration of photoreceptors. _______________________ 1 The price corresponds to the volume-weighted average of the Company's share price on the regulated market of Euronext in Paris over the last eight (8) trading days preceding the date which is three (3) business days prior to publication of the notice of the AGM in the Bulletin d'Annonce Légale Obligatoire, less a 20% discount. View source version on businesswire.com: Contacts GenSight Biologics Chief Financial Officer Ivan Tortet itortet@gensight-biologics.com LifeSci Advisors Investor Relations Guillaume van Renterghem gvanrenterghem@lifesciadvisors.com +41 (0)76 735 01 31 Source: GenSight Biologics S.A. View this news release online at:

临床3期基因疗法

2024-03-22

·药精通Bio

眼科基因治疗行业研究-AAV

嘉宾阵容以及授课话题已曝光，点击图片查询，合作热线：王晨 180 1628 8769文章来源：矩阵生命视界随着基因疗法的发展，AAV（adeno-associated virus）基因治疗已成为治疗眼科疾病的一种新方法。基于AAV的基因治疗具有较高的安全性和有效性，已被证明在一些眼科疾病的治疗中具有良好的疗效。AAV基因治疗是将一个健康的基因通过载体病毒转移到患者的细胞中，从而纠正存在的基因缺陷。AAV是一种不致病的病毒，与人体免疫系统相容性好，因此在临床应用中具有较高的安全性。在眼科领域，AAV基因治疗已被应用于多种疾病的治疗。其中，最广泛应用的是视网膜色素变性症。视网膜色素变性症是一种常见的眼科疾病，由于基因缺陷导致视网膜细胞逐渐死亡，从而导致失明。通过AAV基因治疗，可以将正常的基因导入患者的视网膜细胞中，从而促进视网膜细胞的生长和恢复，改善患者的视力。此外，AAV基因治疗还可以应用于其他眼科疾病的治疗，例如遗传性斑点玻璃体萎缩、角膜病变、青光眼等。这些疾病都与基因缺陷有关，通过AAV基因治疗可以纠正这些基因缺陷，从而治疗疾病。尽管AAV基因治疗在治疗眼科疾病方面具有潜在的优势，但仍需要克服一些挑战。例如，如何确保基因治疗的有效性和安全性，如何最大限度地提高载体病毒的转染率和扩散能力等。此外，如何规范化AAV基因治疗的临床应用也是一个重要问题。随着技术的不断发展，相信AAV基因治疗将成为眼科疾病治疗的一种重要手段。AAV基因疗法的研究历史腺相关病毒（AAV）基因疗法起源于20世纪80年代末期，当时科学家们发现了一种可用于基因递送的非致病性病毒-AAV。随后，研究人员对AAV进行了深入的研究，并发现AAV能够安全、高效地将基因递送至宿主细胞中，因此被广泛应用于基因治疗领域。1965年，AAV首次被发现：美国研究人员在研究腺病毒感染细胞的过程中，发现了一种新型的病毒，即腺相关病毒（AAV）。1984年，AAV基因组被测序：美国研究人员首次测序了AAV的基因组，从而为后续的基因治疗研究提供了重要的基础。P. Tratschin等人首次报道了AAV在哺乳动物体内稳定传递基因的能力，开创了AAV基因治疗的先河。此后，研究人员陆续发现了AAV的多种亚型和血清型，并进一步优化了AAV递送系统的设计和构建，从而使其在基因治疗中的应用变得更为广泛和有效。1990年代，AAV基因载体被开发：研究人员将AAV病毒改造为一种基因载体，用于传递外源基因到人体细胞中，成为AAV基因疗法的关键技术。1993年，菲利普斯等人首次报道了使用AAV递送功能性基因治疗人体的临床试验，标志着AAV基因治疗进入了人体实验阶段。此后，研究人员陆续开展了多项AAV基因治疗的临床试验，并取得了一些积极的治疗效果。2000年代，研究人员开始对AAV基因疗法进行临床试验，主要针对遗传性疾病、神经系统疾病和癌症等领域进行研究。2010年代，AAV基因疗法的研究逐渐成熟：随着技术的不断进步，AAV基因疗法的研究逐渐成熟，取得了一系列重要的研究进展，如提高载体产量、改进递送技术、优化基因治疗方案等。2010年，研究人员利用AAV基因疗法成功治疗了一名患有家族性脂蛋白血症的患者。这是AAV基因疗法在人类临床应用中的一个重要里程碑。2012年，研究人员利用AAV基因疗法成功治疗了一名患有血友病B的患者。这是AAV基因疗法在治疗血液系统疾病方面的一个重要突破。2013年，研究人员利用AAV基因疗法成功治疗了一名患有严重肌无力症的患者。这项研究证明了AAV基因疗法可以用于治疗肌肉和神经系统疾病。2015年，研究人员利用AAV基因疗法成功治疗了一名患有视网膜色素变性症的患者。这是AAV基因疗法在治疗眼科疾病方面的一个重要进展。2016年，研究人员利用AAV基因疗法成功治疗了一名患有囊性纤维化的患者。这项研究证明了AAV基因疗法可以用于治疗常见的遗传性疾病。2017年，研究人员利用AAV基因疗法成功治疗了一名患有克隆氏症的患者。这是AAV基因疗法在治疗免疫系统疾病方面的一个重要突破。2018年，研究人员利用AAV基因疗法成功治疗了一名患有亚急性脊髓联合变性的患者。这项研究证明了AAV基因疗法可以用于治疗。AAV血清型腺相关病毒（AAV）是一种单链DNA病毒，目前已知有超过十种血清型。其中，AAV1~AAV12和AAVrh10是最为常见的AAV血清型。AAV的血清分型是通过对AAV外壳蛋白（VP）的序列分析来进行的。不同的AAV血清型具有不同的递送效率和组织特异性，因此在选择适合的AAV载体用于基因疗法时，需要考虑目标组织的特异性和递送效率。以下是一些常见的AAV血清型及其特点：AAV1：AAV1是最早被发现和应用的AAV血清型之一。它具有较高的递送效率和广泛的组织特异性，被广泛应用于心血管和肌肉系统的基因治疗。此外，AAV1还可以递送到中枢神经系统，并被用于治疗脊髓小脑共济失调、帕金森病和阿尔茨海默病等神经系统疾病。AAV2：AAV2被广泛应用于肝脏、眼部和肺部等组织的基因治疗。AAV2是最早被应用于眼科基因治疗的AAV血清型，它能够稳定地递送基因到视网膜和葡萄膜等眼部组织中，并且具有较低的免疫原性。因此，AAV2被广泛应用于视网膜遗传性疾病的基因治疗，例如Leber遗传性视网膜病变（LCA）和视锥细胞萎缩症等。AAV3：对于神经系统具有较高的递送效率，是神经系统相关疾病的潜在治疗载体。AAV4：与AAV2相似，但其递送效率较低。AAV5：对于肺部和肝脏等组织具有较高的递送效率，可用于治疗呼吸道和肝脏相关疾病。AAV6：对于肌肉组织具有较高的递送效率。AAV7：AAV7在肌肉组织和肝脏中具有较高的递送效率，并且能够穿过血脑屏障递送到中枢神经系统。AAV8：对于肝脏和肌肉组织具有较高的递送效率，是目前广泛应用于肝脏相关基因疗法的载体。AAV9：对于全身性递送和神经系统组织具有较高的递送效率，是近年来研究较为活跃的AAV载体之一。AAV10：对于肝脏、心脏和肺部等组织具有较高的递送效率，可用于治疗相关疾病。AAV11：与AAV2相似，但其递送效率较低。AAV12：最近被发现的一种AAV血清型，对于肌肉和心脏组织具有较高的递送效率。AAVrh10: AAVrh10是一种与猕猴相关的AAV血清型，具有较高的递送效率和广泛的组织特异性，尤其在心脏和肺部中递送基因的效果较为显著。此外，AAVrh10还可以递送到中枢神经系统和肌肉等组织中。AAV2.7m8: AAV2.7m8是一种经过改造的AAV2血清型，具有更高的递送效率和更广泛的组织特异性。研究表明，AAV2.7m8可以在肝脏、心脏、肌肉、肺部和中枢神经系统等多种组织中高效地递送基因。AAV基因疗法的优势AAV基因疗法是一种新型基因治疗方法，它利用非致病性的腺相关病毒作为载体，将治疗所需的基因传递到人体细胞中，以修复或替换缺陷的基因。相比于其他基因疗法，基于AAV的基因疗法优势明显。AAV病毒的基因组相对较小，只有单链DNA，而且AAV病毒不会引起明显的病毒感染或肿瘤形成等副作用，因此具有较高的安全性。AAV基因疗法能够在不影响细胞正常功能的情况下，表达外源基因，使得基因修复或替换的效果更加稳定和长久。AAV病毒在人体内的靶向性强，能够精确地传递基因到治疗所需的细胞或组织中，从而减少对其他细胞和组织的影响。AAV基因疗法可以用于治疗多种疾病，如遗传性疾病、免疫缺陷病、癌症等，因此具有广泛的应用前景。AAV基因疗法面临的挑战AAV基因疗法研究逐渐成熟，随着技术的不断进步，AAV基因疗法的研究逐渐成熟，但是也面临着诸多的挑战。提高AAV递送效率：目前，AAV基因疗法的主要限制之一是递送效率较低。未来研究需要集中精力解决这个问题，以实现更高效的基因治疗。一些研究人员正在探索利用CRISPR/Cas9技术改变细胞表面受体的方法来提高AAV的递送效率。AAV基因转载能力有限：AAV基因载体的基因组结构较小，只能携带较短的外源基因序列，一般只能携带不超过5 kb的外源DNA序列。这种限制使得AAV基因疗法只能用于一些单基因遗传性疾病，如遗传性视网膜病变、囊性纤维化等。对于复杂的多基因疾病，目前还无法直接应用AAV基因疗法进行治疗。因此，目前的研究主要集中在扩大AAV载体携带外源基因序列的能力，或者利用AAV基因载体作为辅助手段，配合其他基因编辑技术（如CRISPR/Cas9）进行治疗。扩大AAV应用范围：虽然AAV基因疗法已经在某些领域取得了成功，但它仍然无法满足许多复杂疾病的治疗需求。因此，未来需要进一步研究如何利用AAV基因疗法来治疗更广泛的疾病，例如癌症、心血管疾病等。开发新型AAV载体：目前，已经发现了多种AAV血清型，每一种AAV血清型都具有不同的递送特点。未来的研究需要开发新型的AAV载体，以适应不同疾病的治疗需求。例如，AAV7和AAV8是在眼科疾病治疗中应用广泛的载体。优化AAV基因疗法的安全性：尽管AAV基因疗法已经证明是相对安全的，但仍然存在一些安全问题，例如免疫反应和肝毒性等。未来的研究需要致力于发展更安全的AAV基因疗法，以确保其在临床应用中的安全性。利用AAV基因疗法进行基因编辑：随着CRISPR/Cas9技术的发展，AAV基因疗法被广泛应用于基因编辑。未来的研究需要进一步深入研究如何利用AAV基因疗法进行精准的基因编辑，以实现更精确、有效的基因治疗。AAV工业生产路径不同的AAV基因治疗药物生产路径可能存在细节差异，具体生产路径应根据所使用的技术和病毒载体等因素进行调整和优化。AAV基因治疗药物生产路径通常可以分为以下几个步骤：AAV载体构建：制备含有治疗基因的AAV载体，现在基因合成技术成熟，成本低，一般直接基因合成。细胞培养：将构建好的AAV载体转染至宿主细胞（通常为HEK293细胞），并进行培养。病毒收集：待宿主细胞达到适当的病毒滴度后，可收集病毒。病毒纯化：通过超滤、柱层析等技术，去除杂质，纯化AAV病毒。病毒浓缩：目前常用的浓缩方法有超滤、离心和冻干等技术。其中，超滤是最常用的方法之一，可以通过不同孔径的滤膜来筛选出病毒颗粒，再利用浓缩设备将病毒颗粒浓缩到所需的浓度。病毒质量控制：对病毒进行质量检测，如细胞毒性检测、感染力检测、病毒纯度检测等。包装及灌装：将病毒进行灌装，通常采用冷冻干燥、液氮冻存等技术，制备成为制剂。临床试验：进行临床试验，包括安全性、有效性等检测。监管审批：通过FDA等相关机构审批，获得上市许可。眼睛是AAV基因治疗的理想器官眼部（尤其是视网膜）是AAV基因疗法的理想场所。眼睛是一个相对"免疫豁免"的空间，即该组织环境可以耐受外源引入的抗原，而不产生炎症免疫反应，有利于外来移植物的长期稳定生存。给药安全性高，因为眼球属于小尺寸的器官，只能使用更小体积和数量的病毒。眼部局部治疗的可行性和可控性也使得基因疗法在这里更加可行和安全。例如，在眼底玻璃体手术中，可以直接将基因疗法载体注射到病变区域，避免了系统性给药带来的潜在不良反应。眼部解剖结构相对简单，相比于其他器官，眼睛的解剖结构相对简单，由少量的细胞类型构成。这使得基因疗法可以针对性地治疗特定的细胞类型或组织，同时也更容易监测治疗效果。眼睛非常适合进行光学检查，光学检查是眼科医生常用的检查方法之一。因此，基因疗法治疗后，可以通过光学检查来监测眼睛的结构和功能变化，为治疗效果的评估提供重要依据。眼睛的神经系统与中枢神经系统相连，但又是一个独立的单元，这使得研究人员可以利用眼睛作为对中枢神经系统的替代研究模型。例如，基因疗法治疗后，可以通过检查病人的眼底反应来判断治疗是否对大脑造成了潜在的影响。AAV基因疗法在眼科疾病中的应用AAV基因疗法是目前眼科领域中最具前景的基因治疗技术之一。眼科疾病通常是由单一的遗传缺陷引起的，而眼睛中的细胞数量和类型也相对较少，因此对于基因疗法的治疗效果更容易进行监测和评估。AAV基因疗法利用非致病性的腺相关病毒（AAV）作为载体，将治疗性基因导入患者的目标细胞中，从而实现对疾病基因的修复或替换。以下是AAV基因疗法在眼科疾病中的应用情况：遗传性视网膜病变：遗传性视网膜病变是一类常见的视网膜疾病，常常导致视力障碍和失明。AAV基因疗法已经成功用于治疗多种遗传性视网膜病变，例如Leber遗传性视网膜病变、视网膜素蛋白缺乏症等。临床研究表明，AAV基因疗法可以显著改善患者的视力和生活质量。黄斑变性：黄斑变性是老年性黄斑病变的一种，是导致视力丧失的主要原因之一。AAV基因疗法已经成功用于治疗一些黄斑变性患者，例如利用AAV2载体导入RPE65基因，以恢复视网膜色素的合成。临床试验结果显示，该治疗方案可以显著改善患者的视力和生活质量。夜盲症：夜盲症是一类遗传性视网膜疾病，常常导致夜间视力障碍。AAV基因疗法已经成功用于治疗一些夜盲症患者，例如利用AAV2载体导入RPE65基因，以恢复视网膜色素的合成。临床试验结果显示，该治疗方案可以显著改善患者的夜间视力。视网膜色素变性：视网膜色素变性是一类遗传性视网膜疾病，常常导致视力障碍和失明。AAV基因疗法已经成功用于治疗一些视网膜色素变性患者，例如利用AAV2载体导入BEST1基因，以恢复细胞膜通透性。临床试验结果显示，该治疗方案可以显著改善患者免疫调节：AAV基因疗法还可以被用于调节免疫系统，例如治疗自体免疫性疾病、眼部过敏等。通过向免疫细胞输送调节基因，可以调节免疫系统的反应，从而缓解免疫反应引起的炎症和疾病。新型治疗方法：AAV基因疗法还可以被用于开发新型治疗方法，例如治疗白内障、青光眼等。通过向受影响的细胞输送合适的基因或RNA，可以促进细胞的修复和再生，从而缓解或治愈眼部疾病。AAV基因疗法在眼科疾病中的一些应用案例：Leber's congenital amaurosis (LCA)治疗：LCA是一种罕见的遗传性疾病，患者的视网膜细胞无法正常工作，导致失明。2008年，美国宾夕法尼亚大学和瑞士伯尔尼大学的研究人员首次使用AAV基因疗法治疗LCA。研究人员将AAV2载体携带RPE65基因注入患者视网膜，结果患者的视力得到了显著改善，这是第一次AAV基因疗法在人类身上的成功案例。X连锁遗传性视网膜色素变性：AAV2.7m8-hGRK1-RPGR基因疗法在临床试验中显示出较高的安全性和疗效，已获得美国FDA批准进入III期临床试验。成年人的先天性色盲：一项初步的IIa期临床试验表明，AAV2.7m8-hGRK1-OPN1LW基因疗法可以在人类视网膜中安全有效地表达红色感光蛋白，从而显著提高色盲患者的色觉能力。红绿色盲：一个小型的I/II期临床试验表明，AAV2.7m8-hGRK1-OPN1MW基因疗法可以显著改善患者的色觉能力，而且安全性良好。遗传性视神经萎缩：一个小型的I/II期临床试验表明，AAV2.7m8-hGRK1-NMNAT1基因疗法可以减缓遗传性视神经萎缩的进程，而且安全性良好。失明：一项初步的I/II期临床试验表明，AAV2.7m8-hGRK1-CNGA3基因疗法可以显著提高ACHM患者的视力，而且安全性良好。视网膜色素变性：AAV2.7m8-hGRK1-RPE65基因疗法已经在临床试验中显示出很好的疗效和安全性，并被美国FDA批准为第一种基因疗法上市。色素上皮脱离：一个小型的I/II期临床试验表明，AAV2.7m8-hGRK1-RPE65基因疗法可以显著提高患者的视力，而且安全性良好。AAV基因疗法在眼科疾病中面临的挑战AAV基因疗法在治疗眼科疾病方面具有很大的潜力，但也面临着许多挑战和限制。未来的研究需要更多地关注这些问题，以实现更好的治疗效果和安全性。治疗效果的持久性：AAV基因疗法的治疗效果需要持续的基因表达，但由于AAV病毒粒子不可复制，治疗效果可能会逐渐减弱或消失，需要进行多次治疗。免疫反应：由于AAV基因疗法需要通过体内注射病毒颗粒来实现，因此可能引起宿主免疫系统的反应，特别是针对病毒载体的抗体，这可能会降低疗效。病变复杂性：眼科疾病的治疗通常需要针对复杂的病理生理过程，例如对多个细胞类型的影响，需要实现高度特异性和精准性，目前的技术难以完全满足这种需求。安全性问题：虽然AAV病毒被认为是相对安全的基因递送载体，但仍然存在潜在的安全问题，例如基因转移的意外效应或突变的可能性，需要进行进一步的安全性评估和监测。成本问题：目前，AAV基因疗法仍处于研究阶段，需要进行大量的前期工作，例如载体设计、生产和纯化、浓缩等，这些工作需要高昂的成本支持。愿景AAV基因疗法在眼科领域已经取得了很多重要的突破，但仍然面临许多挑战。未来，随着基因编辑和基因治疗技术的不断发展，AAV基因疗法在眼科疾病治疗中的应用前景非常广阔。新的AAV血清型的发现将进一步扩大AAV基因疗法的应用范围，有可能改变目前基因治疗仅能治疗特定疾病的现状。基因编辑技术（如CRISPR/Cas9）与AAV基因载体相结合，有望实现更精准的基因矫正和治疗。AAV基因载体的转染效率仍然不够高，尤其是对于难以转染的细胞类型，如视网膜色素上皮细胞。因此，未来需要进一步研究和开发更加有效的目标细胞转染技术。在AAV基因疗法的临床应用过程中，需要保证其安全性和长期稳定性，避免不良反应和基因载体的漂移。因此，未来需要进一步研究和完善AAV基因载体的安全性和稳定性，以便更好地应用于临床治疗。总之，AAV基因疗法在眼科疾病治疗中的应用前景非常广阔，未来的研究和开发将进一步促进其在眼科疾病治疗中的应用。嘉宾阵容以及授课话题已曝光，点击图片查询，合作热线：王晨 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基因疗法

2023-06-13

·PipelineReview

Adverum Biotechnologies Grants License to Ray Therapeutics Inc. for the AAV.7m8 Intravitreal Capsid

Adverum has granted Ray Therapeutics a non-exclusive, royalty-bearing license for the use of Adverum’s proprietary intravitreal AAV.7m8 vector capsid together with RayTx’s RTx-015 asset REDWOOD CITY, CA, USA I June 12, 2023 I Adverum Biotechnologies, Inc. (Nasdaq: ADVM), a clinical-stage company that aims to establish gene therapy as a new standard of care for highly prevalent ocular diseases, announces an agreement granting Ray Therapeutics a non-exclusive, royalty bearing license of Adverum’s proprietary AAV.7m8 intravitreal (IVT) vector capsid to be used in conjunction with Ray’s optogenetics payload. “This deal highlights the value of Adverum’s AAV.7m8 gene therapy platform, a capsid for IVT delivery, in a variety of ocular gene therapy indications,” commented Laurent Fischer, M.D., president and chief executive officer of Adverum Biotechnologies. “A single IVT injection of Ixo-vec in the Phase 1 OPTIC study for wet age-related macular degeneration has been well tolerated and has led to stable and persistent aflibercept protein levels through at least three years. Ixo-vec is currently being evaluated in the ongoing Phase 2 LUNA trial. This marks the sixth asset delivered via AAV.7m8, including our Ixo-vec candidate for the treatment of wet age-related macular degeneration, Gensight’s GS030, an optogenetic asset for retinitis pigmentosa, both of which have shown promising results in early clinical trials, as well as Adverum’s own investigational pre-clinical pipeline assets in dry AMD, optogenetics and blue cone monochromacy.” “Visual optogenetics is a disruptive technology which affords the opportunity to restore life-transforming levels of vision to blind and visually impaired patients with conditions such as retinitis pigmentosa,” said Paul Bresge, chief executive officer of Ray Therapeutics. “We have developed a next generation bioengineered optogenetic payload which we believe is optimized for human vision. When delivered using previously studied low doses of AAV.7m8, we anticipate levels of target retinal ganglion cell transduction that could realize the full potential of our RTx-015 asset.” Under the terms of the agreement, Adverum grants Ray Therapeutics a worldwide, non-exclusive license of AAV.7m8 for the prevention, treatment, diagnosis or amelioration of any ocular disorder utilizing Ray’s optogenetics approach. About Adverum Biotechnologies Adverum Biotechnologies (NASDAQ: ADVM) is a clinical-stage company that aims to establish gene therapy as a new standard of care for highly prevalent ocular diseases with the aspiration of developing functional cures to restore vision and prevent blindness. Leveraging the capabilities of its proprietary, intravitreal (IVT) platform, Adverum is developing durable, single-administration therapies, designed to be delivered in physicians’ offices, to eliminate the need for frequent ocular injections to treat these diseases. Adverum is evaluating its novel gene therapy candidate, ixoberogene soroparvovec (Ixo-vec, formerly referred to as ADVM-022), as a one-time, IVT injection for patients with neovascular or wet age-related macular degeneration. Additionally, by overcoming the challenges associated with current treatment paradigms for debilitating ocular diseases, Adverum aspires to transform the standard of care, preserve vision, and create a profound societal impact around the globe. For more information, please visit www.adverum.com . About Ray Therapeutics Ray Therapeutics is developing novel optogenetics gene therapies for patients with blinding diseases. The company is developing its lead candidate RTx-015 in retinitis pigmentosa, a degenerative retinal disease with significant unmet medical need. The company’s mission is to use optogenetics to restore vision, independent of genetic mutation for patients with inherited retinal diseases. Ray Therapeutics is based in San Francisco, California. For additional information, visit www.raytherapeutics.com . SOURCE: Adverum Biotechnologies

基因疗法引进/卖出临床1期临床2期

100 项与 GS030 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
视网膜色素变性	临床2期	美国	Gensight Biologics SA	2018-09-26
视网膜色素变性	临床2期	法国	Gensight Biologics SA	2018-09-26
视网膜色素变性	临床2期	英国	Gensight Biologics SA	2018-09-26

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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


GS030 (ASGCT2016)	N/A	腱鞘囊肿	-	AAV2.7m8-ChrimsonR-tdTomato (GS030-DP)	鏇構觸齋範鹹糧壓蓋遞(鹹膚蓋醖構鏇觸鬱選鬱) = 壓範襯選積築獵艱蓋鏇蓋簾窪範鏇簾餘築網糧 (壓襯艱艱淵鹹蓋獵築鏇 )	积极	2016-05-01
ARVO2016	N/A	-	-	ChrimsonR	簾窪餘齋衊構艱簾蓋齋(淵選膚鏇膚積獵憲夢範) = 範壓廠顧醖艱齋範範鏇顧選製顧製蓋遞網簾醖 (壓鑰製鏇壓遞願鏇獵網, 0.72) 更多	-	2016-05-01