Tominersen

Using RNA to interfere with a gene’s expression of disease-causing proteins is a validated therapeutic approach, but so far, the products in this drug class only address liver proteins. Reducing levels of certain proteins in the central nervous system could offer a new way to treat neurological disorders. The challenge facing drug developers is getting these therapies deep into the brain. Atalanta Therapeutics has technology that delivers RNA interference therapies into the CNS. The startup has spent the past four years quietly working on its technology and potential drugs. On Tuesday, Atalanta revealed two lead programs for rare neurological disorders that currently have no FDA-approved therapies. The Boston-based startup also announced $97 million in financing to advance those programs to the clinic and support other CNS therapies in its pipeline. An RNA interference (RNAi) therapy uses small pieces of non-coding RNA to block how certain genes are expressed. In 2018, Alnylam Pharmaceuticals’ Onpattro became the first FDA-approved RNAi drug. This therapy is delivered inside a lipid nanoparticle, which preferentially goes to liver cells. Alnylam and others have been pursuing ways to bring RNAi to the CNS. Sponsored Exclusive Improving the Healthcare Financial Experience to Help Care Flow Zelis CEO Amanda Eisel shares her perspective on how the company is solving the problems of a fragmented health financial system to benefit all. By Stephanie Baum Atalanta, named for the mythical Greek huntress, makes its therapies with oligonucleotides, short pieces of synthetic RNA. Early efforts in oligo and RNAi drugs could not get beyond the outer layer of the brain, Atalanta CEO Alicia Secor said. One of Atalanta’s founders is Craig Mello, a professor in the RNA Therapeutics Institute at the University of Massachusetts Medical School who was awarded the 2006 Nobel Prize in Physiology or Medicine for his RNAi discoveries. Mello’s research includes ways to deliver oligo therapies into the brain. Atalanta does not use lipid nanoparticles or other delivery technologies, Secor said. Instead, the startup’s drugs employ what she described as a divalent structure in which two small-interfering RNA (siRNA) duplexes are joined by a linker. This structure enable the therapy get into the CNS and it imbues the therapy with properties such as potency and durability. “These molecules are very special and have demonstrated the ability to achieve really broad brain distribution in all regions, [and] importantly, deep brain penetration,” Secor said. Mello was particularly interested in developing therapies for Huntington’s disease, a rare neurological disorder that originates deep in the brain. UMass research published in Nature Biotechnology in 2019 described mouse and monkey studies that showed a single injection of divalent siRNA led to silencing of the gene that causes Huntington’s. This silencing lasted at least six months. Sponsored Sponsored Post The Funding Model for Cancer Innovation is Broken — We Can Fix It Closing cancer health equity gaps require medical breakthroughs made possible by new funding approaches. By Eve McDavid - CEO of Mission-Driven Tech Soon after the research was published, F-Prime Capital licensed the UMass technology and formed Atalanta with Secor as its first employee. When the startup emerged from stealth in 2021 with $110 million in Series A financing, it also revealed R&D alliances with Biogen and Genentech. Secor acknowledged that it’s unusual for a startup to land two big pharma partnerships at such an early stage, but she said the deals speak to the industry interest in bringing RNAi to the brain. The alliances provided Atalanta with non-dilutive capital that enabled the company to embark on additional preclinical research that further de-risked its technology platform, Secor said. CNS targets of the Genentech partnership remain undisclosed. Huntington’s was part of the Biogen alliance, but Secor said that agreement is unwinding “for business reasons.” Atalanta now has full control of the Huntington’s programs, one of which the startup aims to advance to human testing later this year. Other companies are further along in development with Huntington’s drug candidates. Last month, Novartis agreed to pay $1 billion for rights to a PTC Therapeutics small molecule on track for pivotal testing. Roche and Ionis Pharmaceuticals are partners in the development of tominersen, an antisense oligonucleotide (ASO) that has weathered clinical trial setbacks. Secor describes Atalanta’s technology as a more efficient way of selectively delivering a potent Huntington’s therapy into the brain. “There is no other oligonucleotide that has been able to achieve what we have in terms of knockdown and durability,” Secor said. “I think most people would argue ASO chemistry is good, but RNAi is the next generation.” The other Atalanta program on track to the clinic is a potential treatment for a rare form of epilepsy driven by gain-of-function variants in the KCNT1 gene. Patients who have this disease can experience 50 to 100 seizures daily that aren’t treatable with existing anti-seizure drugs, Secor said. Atalanta’s therapy is designed to reduce levels of KCNT1 protein. In mouse studies, a 50% reduction in protein led to a 70% reduction in seizures, Secor said. Evaluating safety is the main goal of the planned Phase 1 test of the KCNT1 therapy, but this study will also enable Atalanta to quickly demonstrate its technology can work in humans. That’s because seizure activity can also be measured. Reducing seizures in the trial will provide some clinical proof of concept for the drug, and for Atalanta’s technology, Secor said. Atalanta’s latest financing is a Series B round co-led by EQT Life Sciences and Sanofi Ventures. Other participants include new investors RiverVest Venture Partners, Novartis Venture Fund, funds managed by abrdn Inc, Pictet Alternative Advisors, Mirae Asset Financial Group, and GHR Foundation alongside earlier investor F-Prime Capital. Besides the Huntington’s and KCNT1 programs, the Atalanta pipeline currently spans Alzheimer’s disease, pain, and unspecified CNS disorders driven by multiple undisclosed targets. Atalanta is not actively looking for more partners right now, but Secor is leaving the door open. “We’ve got a pretty powerful platform that can basically knock down any transcript in the brain where there’s genetic validation that it’s disease causing,” she said. “There’s a whole universe of targets and we are open to inbound interest. Right now, we’re focused on filing our [investigational new drug applications]. But you know, we might be open [to partnerships] in 2025.” Image by Atalanta Therapeutics

近日，一项来自于麻省理工学院和哈佛大学博德研究所的研究表明，业内一直以来关于亨廷顿舞蹈症的开发方式可能搞错了。 相关研究发表于Cell上。 业内开发方向 一直以来，亨廷顿舞蹈症的病因被认为是亨廷顿基因（HTT）突变。正常情况下，该基因内包含一段CAG（胞嘧啶、腺嘌呤和鸟嘌呤）三核苷酸重复序列，能够编码一种功能不明，但似乎非常重要的蛋白质，当这段CAG重复序列的数量在患者中年时期异常增加时，就会导致亨廷顿病的发生。此时被称为纹状体投射神经元（SPN）的神经细胞开始死亡。这会引发一系列运动和认知症状，最终导致患者失去生命。 然而为什么CAG重复序列增加就会导致亨廷顿病发，一直是研究领域的空白。 虽然如此，业内的开发方向基本上围绕着HTT的突变蛋白展开。 例如诺华在去年12月看上了PTC Therapeutics的PTC518，这是一种HTT剪接调节剂，作为小分子药物具有穿透血脑屏障的能力，可以显著减少突变HTT蛋白。 另外还有uniQure公司的AMT-130，能够通过AAV5载体携带专门沉默HTT基因表达的基因来治疗该疾病。 虽然说方法多种多样，但是核心主旨仍然是围绕沉默，抑制突变的HTT蛋白展开。然而现在的这项研究却表明，抑制HTT蛋白或许为时已晚。 为时已晚 为了探究CAG重复片段是如何导致亨廷顿病的，以Steven McCarroll为首的研究人员检查了处于疾病不同阶段去世的患者大脑中的纹状体投射神经元。令他们惊讶的是，他们发现患者一生中亨廷顿基因的CAG重复片段长度会增加，起初增长缓慢，但在达到约80个重复片段后迅速增加。 而后期进展会越来越快，一开始是以10年为单位增长，接下来是以年为单位增长，到最后就会以月为单位迅速增长。 不过，这种重复增长在基因突变至超过150个重复片段之前对患者影响不大。而150个重复片段以后，原本在纹状体投射神经元中沉默的其他基因开始激活，包括参与程序性细胞死亡的基因。 因此，只有在重复的CAG序列足够长之后，这种蛋白才会呈现出毒性。 但是研究人员认为，一旦出现了毒性，想要拯救患者可能就为时已晚了。降低突变蛋白拯救不了已经进入迈向死亡倒计时的细胞。 所以降低亨廷顿突变蛋白表达可能就不是治疗的理想方法，而且实际上早先有许多围绕降低亨廷顿蛋白突变的疗法临床失败，很可能就是这个原因。 作者认为，治疗可以侧重于减缓重复片段的增长；考虑到重复片段达到有毒长度需要很长时间，即使只是适度减缓体细胞扩张，也可能大大推迟亨廷顿病症状的出现。 总结 总的来说，这项研究或许可以改变业内对于亨廷顿病治疗方法的开发方向，从原本的抑制突变蛋白，转向减少重复片段增长。 这也可能为我们解答了，为什么此前罗氏和Ionis开发的tominersen明明降低了脑脊液中突变亨廷顿蛋白的水平，但是仍然没有获益的情况。Wave Life Sciences公司的WVE-003被武田放弃的理由也可能与此有关。 不过，这也意味着许多在研管线，可能因此出现大洗牌或大裁撤，例如上文提到的诺华和PTC预付10亿美元的合作。 参考来源： https://www.cell.com/action/showPdf?pii=S0092-8674%2824%2901379-5