Antisense Oligonucleotide (ASO) Development for Rare and Neglected Diseases

针对罕见和被忽视疾病的反义寡核苷酸 (ASO) 开发

基本信息

项目摘要

We have engaged in productive partnerships across various therapeutic areas in collaboration with NIH and external academic researchers and companies. During the current fiscal year, progress was made in meeting the objectives of these various collaborations. The team is further refining the high-content ASO screening assays utilizing organoids. Complementing this work, algorithms to analyze the data from these assays are under active development in collaboration with the informatics team and confirm the ability of these data to predict toxicity accurately. The animal toxicity experiments of the ASOs were initiated to benchmark the high-content screening assays. In collaboration with clinical groups at the NIH Clinical Center, the design of the clinical trial is underway and will shortly be submitted for consideration. ASO Toxicity Assay Development: We continue refining the high-content screening assays using cell-based platforms that will substitute for low-throughput animal toxicity experiments. These screening platforms rely on organoids to predict the toxic side effects of ASOs and improve the safety pharmacology of this drug class. In parallel, we are constructing and benchmarking algorithms that predict toxicity, allowing bad ASOs to be eliminated early in the design phase. In this way, we are speeding up the process of ASO development and making it cheaper and faster to produce disease-modifying therapies for rare diseases. We collaborate with pharmaceutical companies and academic researchers to achieve these ambitious targets. For example, we continue to work with Ionis Pharmaceuticals and Roche, two of the leaders in the ASO field, on our in vitro and in vivo screening platform development. Our approach will make the domain knowledge accessible to all stakeholders. We are collaborating on developing and validating 2D and 3D human cell-based ASO toxicity assays using in vitro and nonclinical in vivo toxicity and safety data our collaborators have previously generated. We have incorporated iPSC-derived human neuronal cells into the development of these assays. The approach supports using a patient's cells in future IND-directed safety and toxicity studies for N=1 or a few diseases. Development of a Predictive Model of Safety and Toxicity of Candidate ASO Therapies: In collaboration with Charles River laboratories and our pharmaceutical partners, we continue to develop a platform to evaluate the safety and acute toxicity of ASOs in mice. These animal data have been compared to the results of cell-based screening assays and have validated the ability of the in vitro assays to predict the toxicity properties of ASOs in animals and to rely on the in vitro cell-based studies for future safety readouts. The project's initial focus is on acute and chronic dose-limiting toxicities encountered following intrathecal administration of ASOs targeting CNS neurological disorders. Our screening assay reduces the need for future animal experimental testing and predicts the safety of prospective candidate ASOs intended for clinical use. This project aims to provide sufficient and confirmatory in vivo data to the point that the FDA accepts cell-based in vitro data instead of conventional animal toxicology studies currently required for advancing new ASOs to clinical trials. N=1 Gene Identification in Neurodegenerative and Systemic Rare Diseases: Individualized N=1 therapies target a minimal number of people, even as few as one. We continue to work with the N=1 Collaborative, academia, foundations, and biotech companies to bring customizable treatments targeting the underlying genetic defect as safely and quickly as possible in rare diseases. We are focused on using antisense oligonucleotides (ASOs), as they are rapidly customizable, cost-efficient to manufacture, straightforward to administer and have a growing safety and efficacy record. Through these efforts, we are establishing a standardized framework for individualized medicine that will extend to other customizable platform technologies such as siRNAs, RNA therapeutics, and CRISPR. To test our drug development pipeline, we are working on two genes, KIF5A and CHCHD10, that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as demonstration projects. ALS is a rare neurodegenerative disease characterized by progressive loss of motor neurons leading to respiratory failure and death. Approximately 7,000 Americans die of ALS yearly, which will increase dramatically in the future because of population aging. In collaboration with Dr. Derek Narendra (NINDS) and Dr. Justin Kwan, the director of the NINDS ALS clinic at the NIH Clinical Center, we work on developing ASOs and screening assays to identify lead ASOs for both genes and perform the IND-enabling studies with the aim of clinical trials. ASO Delivery Development: Most rare diseases affect the central nervous system, meaning gene therapies such as ASOs must be delivered intrathecally. While manageable, this route of administration adds to the complexity when scaling up treatments within the general rare disease population. We explore advanced delivery approaches, such as lipid nanoparticles, chemical structure, and conjugation with targeting moieties. Each system shows promise, but the goal of oral delivery of gene therapy agents requires considerable ongoing effort. The resources at NCATS bring key competencies to speed up research on delivery approaches. For example, we collaborate with Optimeos Life Sciences to apply their tunable lipid nanoparticle technology to deliver ASOs. We are working on in vitro and in vivo experiments to explore additional aspects of this innovative delivery system to neurons and other tissues. Together, we are exploring this payload delivery method to decrease the dose and mitigate the toxicity of ASOs. If successful, this novel modality will empower the ASO field to find a safe way to distribute this new class of therapeutics to target tissues. Initial experiments demonstrate the uptake of the nanoparticles into neurons and other cell types, highlighting the potential value of this new delivery approach. ASO Development for Infectious Diseases: In addition to treating rare diseases, we also deploy ASO technologies to treat emerging viruses. In particular, we are using ASOs to knock down the viral replication of SARS-CoV-2. This project collaborates with colleagues in the Early Translation Branch (ETB) at NCATS and Dr. Avindra Nath at NINDS. This effort maps out regions of the viral genome that are amenable to RNA-directed therapies. The underlying notion is that this approach can be more broadly applied to emerging pathogens once their genomic sequence has been isolated. In collaboration with biotech companies, we are also working on ASO liver and systemic toxicity discovery and assay development to test the candidate ASOs for infectious diseases.
我们与 NIH 以及外部学术研究人员和公司合作,在各个治疗领域建立了富有成效的合作伙伴关系。在本财政年度,在实现这些各种合作的目标方面取得了进展。该团队正在利用类器官进一步完善高内涵 ASO 筛选测定。作为这项工作的补充,我们正在与信息学团队合作积极开发分析这些测定数据的算法,并确认这些数据准确预测毒性的能力。 ASO 的动物毒性实验是为了对高内涵筛选测定进行基准测试。与 NIH 临床中心的临床小组合作,临床试验的设计正在进行中,并将很快提交审议。 ASO 毒性测定开发:我们继续使用基于细胞的平台改进高内涵筛选测定,以替代低通量动物毒性实验。这些筛选平台依靠类器官来预测 ASO 的毒副作用并提高此类药物的安全药理学。与此同时,我们正在构建预测毒性的算法并对其进行基准测试,从而在设计阶段的早期就消除不良的 ASO。通过这种方式,我们正在加快 ASO 的开发进程,并使罕见疾病的疾病缓解疗法的生产变得更便宜、更快捷。我们与制药公司和学术研究人员合作,以实现这些雄心勃勃的目标。 例如,我们继续与 ASO 领域的两家领导者 Ionis Pharmaceuticals 和 Roche 合作开发我们的体外和体内筛选平台。我们的方法将使所有利益相关者都能获取领域知识。我们正在合作开发和验证基于 2D 和 3D 人类细胞的 ASO 毒性测定,使用我们合作者之前生成的体外和非临床体内毒性和安全性数据。我们已将 iPSC 衍生的人类神经元细胞纳入这些测定的开发中。该方法支持在未来针对 N=1 或几种疾病的 IND 导向的安全性和毒性研究中使用患者的细胞。 开发候选 ASO 疗法的安全性和毒性预测模型:我们与 Charles River 实验室和我们的制药合作伙伴合作,继续开发一个平台来评估 ASO 在小鼠中的安全性和急性毒性。这些动物数据已与基于细胞的筛选测定的结果进行了比较,并验证了体外测定预测 ASO 在动物中的毒性特性的能力,并依赖于体外基于细胞的研究来获得未来的安全性读数。 该项目最初的重点是针对中枢神经系统神经系统疾病的 ASO 鞘内给药后遇到的急性和慢性剂量限制毒性。我们的筛选分析减少了未来动物实验测试的需要,并预测了用于临床用途的潜在候选 ASO 的安全性。该项目旨在提供充足且验证性的体内数据,以使 FDA 接受基于细胞的体外数据,而不是目前将新 ASO 推进临床试验所需的传统动物毒理学研究。 神经退行性疾病和系统性罕见疾病中的 N=1 基因鉴定:个体化 N=1 疗法针对极少数人,甚至只有一个人。我们继续与 N=1 Collaborative、学术界、基金会和生物技术公司合作,尽可能安全、快速地针对罕见疾病的潜在遗传缺陷提供可定制的治疗方法。 我们专注于使用反义寡核苷酸 (ASO),因为它们可快速定制、制造成本效益高、管理简单,并且具有不断增长的安全性和有效性记录。通过这些努力,我们正在建立个体化医疗的标准化框架,该框架将扩展到其他可定制的平台技术,例如 siRNA、RNA 疗法和 CRISPR。 为了测试我们的药物开发渠道,我们正在研究两种基因:KIF5A 和 CHCHD10,它们会导致肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 作为示范项目。 ALS 是一种罕见的神经退行性疾病,其特征是运动神经元进行性丧失,导致呼吸衰竭和死亡。每年约有 7,000 名美国人死于 ALS,由于人口老龄化,这一数字在未来还将急剧增加。我们与 Derek Narendra 博士 (NINDS) 和 NIH 临床中心 NINDS ALS 诊所主任 Justin Kwan 博士合作,致力于开发 ASO 和筛选测定法,以确定两个基因的先导 ASO 并执行 IND 启用以临床试验为目的的研究。 ASO 递送开发:大多数罕见疾病都会影响中枢神经系统,这意味着 ASO 等基因疗法必须鞘内递送。虽然易于管理,但这种给药途径增加了在一般罕见病人群中扩大治疗规模的复杂性。我们探索先进的递送方法,例如脂质纳米粒子、化学结构以及与靶向部分的缀合。每个系统都显示出希望,但口服递送基因治疗药物的目标需要相当大的持续努力。 NCATS 的资源带来了加速交付方法研究的关键能力。例如,我们与 Optimeos Life Sciences 合作,应用他们的可调脂质纳米颗粒技术来提供 ASO。我们正在开展体外和体内实验,以探索这种创新的神经元和其他组织递送系统的其他方面。我们正在共同探索这种有效负载输送方法,以减少 ASO 的剂量并减轻其毒性。如果成功,这种新颖的方式将使 ASO 领域能够找到一种安全的方法,将这种新型疗法分配到目标组织。初步实验证明纳米粒子被神经元和其他细胞类型吸收,凸显了这种新的递送方法的潜在价值。 针对传染病的ASO开发:除了治疗罕见疾病,我们还部署ASO技术来治疗新出现的病毒。特别是,我们正在使用 ASO 来抑制 SARS-CoV-2 的病毒复制。该项目与 NCATS 早期翻译分部 (ETB) 的同事和 NINDS 的 Avindra Nath 博士合作。这项工作绘制了病毒基因组中适合 RNA 导向疗法的区域。基本概念是,一旦分离出新出现的病原体的基因组序列,这种方法就可以更广泛地应用于它们。我们还与生物技术公司合作,致力于 ASO 肝脏和全身毒性的发现和检测开发,以测试候选 ASO 是否适用于传染病。

项目成果

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Elizabeth Ottinger其他文献

Elizabeth Ottinger的其他文献

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{{ truncateString('Elizabeth Ottinger', 18)}}的其他基金

LUM-001 as a Treatment for Creatine Transporter Deficiency
LUM-001 治疗肌酸转运蛋白缺乏症
  • 批准号:
    9551295
  • 财政年份:
  • 资助金额:
    $ 108.8万
  • 项目类别:
A Protein Replacement Drug for Friedreichs Ataxia
弗里德赖希共济失调的蛋白质替代药物
  • 批准号:
    9551920
  • 财政年份:
  • 资助金额:
    $ 108.8万
  • 项目类别:
Developing an Integrated Rare Disease Bioinformatics Resource to Determine Phenotype to Genotype Correlations
开发综合罕见病生物信息学资源以确定表型与基因型的相关性
  • 批准号:
    10910762
  • 财政年份:
  • 资助金额:
    $ 108.8万
  • 项目类别:
COVID-19: Identification and Development of Clinical Candidates to Treat SARS-CoV-2
COVID-19:识别和开发治疗 SARS-CoV-2 的临床候选药物
  • 批准号:
    10910766
  • 财政年份:
  • 资助金额:
    $ 108.8万
  • 项目类别:
A Treatment for Patients with Jansens Metaphyseal Chondrodysplasia
Jansens 干骺端软骨发育不良患者的治疗
  • 批准号:
    10253937
  • 财政年份:
  • 资助金额:
    $ 108.8万
  • 项目类别:
Evaluation of ACT1 to Treat Diabetic Keratopathy
ACT1 治疗糖尿病角膜病的评价
  • 批准号:
    10910753
  • 财政年份:
  • 资助金额:
    $ 108.8万
  • 项目类别:
Developing an Integrated Rare Disease Bioinformatics Resource to Determine Phenotype to Genotype Correlations
开发综合罕见病生物信息学资源以确定表型与基因型的相关性
  • 批准号:
    10255329
  • 财政年份:
  • 资助金额:
    $ 108.8万
  • 项目类别:
CincY as a Treatment for Creatine Transporter Defect
CincY 治疗肌酸转运蛋白缺陷
  • 批准号:
    9205570
  • 财政年份:
  • 资助金额:
    $ 108.8万
  • 项目类别:
Development of the Novel Antifungal VT-1129 for Cryptococcal Meningitis
开发治疗隐球菌性脑膜炎的新型抗真菌药物 VT-1129
  • 批准号:
    9205571
  • 财政年份:
  • 资助金额:
    $ 108.8万
  • 项目类别:
A Treatment for Patients with Jansens Metaphyseal Chondrodysplasia (JMC)
Jansens 干骺端软骨发育不良 (JMC) 患者的治疗方法
  • 批准号:
    10685888
  • 财政年份:
  • 资助金额:
    $ 108.8万
  • 项目类别:

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