Manufacture of an intracerebroventricular Enzyme Replacement Therapy for CLN1 Batten Disease

CLN1巴顿病脑室内酶替代疗法的研制

基本信息

批准号：
10641950
负责人：
SEAN EKINS
金额：
$ 149.99万
依托单位：
COLLABORATIONS PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641950
关键词：
Affect Age Months Animals Behavioral Beta-glucuronidase Biochemical Biodistribution Biological Products Biological Sciences Biotechnology Blindness Brain Brain region Brazil CLN1 gene CLN2 gene Canis familiaris Caring Cell Line Cessation of life Child Childhood Chinese Hamster Ovary Cell Clinic Clinical Clinical Pathology Clinical Research Clinical Trials Clone Cells Code Collaborations Communication Contracts Data Dementia Deterioration Development Disease Documentation Dose Enzymes Epilepsy Family Feedback Formulation Future Gait Genes Health system Hospitalization Human Immune Immunoassay Immunotoxicology Infantile neuronal ceroid lipofuscinosis Innovation Corps International Investments Laboratories Letters Licensing Live Birth Lysosomal Storage Diseases Marketing Measures Medical Genetics Mole the mammal Motor Mus Mutation Nerve Degeneration Neuronal Ceroid-Lipofuscinosis Ophthalmology Orphan Drugs Outcome Measure Palliative Care Patients Pharmacologic Substance Phase Phase I/II Clinical Trial Physicians Population Positioning Attribute Prevalence Process Proteins Rare Diseases Rattus Recombinants Recovery Reporting Retina Role Rotarod Performance Test Route Safety Seizures Small Business Innovation Research Grant Spielmeyer-Vogt Disease Spinal Cord Taxes Testing Therapeutics for Rare and Neglected Diseases Toxic effect Toxicology Translating Translations United States National Institutes of Health Update Work Writing antibody detection clinical trial protocol commercialization cost diagnostic tool disease phenotype enzyme activity enzyme pathway enzyme replacement therapy experience fighting gene therapy glycosylation hospital services improved in vivo infancy interest intravenous administration manufacture neuron loss neuropathology phenotypic data programs thioesterase PPT1 gene product treatment effect voucher young adult

项目摘要

Summary The neuronal ceroid lipofuscinoses (NCLs) are a group of incurable neurodegenerative storage disorders primarily affecting the brain and the retina of children and young adults, leading to dementia, blindness, epilepsy, and early death, with a prevalence of approximately 1.5 to nine per million population (1.3 to 7 per 100,000 live births). The infantile onset form CLN1 disease is caused by mutations in the CLN1/PPT1 gene, which codes for the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1) resulting in a reduction or absence of enzyme activity. CLN1 disease usually presents between 6 and 24 months of age and there are 2-3 children with this form identified each year and currently 24 known children with CLN1 in the US and 11 in Brazil (with likely many more undiagnosed). There are currently no treatments available other than palliative therapies and the disease is fatal. Human recombinant PPT1 (rhPPT1) expressed in CHO cells has been previously reported to modify disease phenotypes following a single intrathecal (IT) and intravenous (IV) administration in PPT1 deficient mice (Ppt1-/-). After successful completion of our Phase I SBIR in which we met or exceeded our milestones IT, intracerebroventricular (ICV) as well as combined routes of delivery were compared. We demonstrated that monthly administration of rhPPT1 via ICV produced statistically significant treatment effects in Ppt1-/- mice, such as rescue of more than 60% PPT1 enzyme activity decreased secondary enzyme levels, decreased the loss of neurons in all regions of brain and spinal cord and improved gait and rotarod results. This also illustrated that delivery of enzyme via this route alone may be sufficient rather than using in combination with IT dosing. We have now developed our own PPT1 cell line using CHO-DG44, that is scalable for GMP manufacture and performed initial purification development strategies and we are developing a diagnostic tool for CLN1. The CLN1 ERT data clearly points to ICV dosing as ideal for future studies, which is also a preferred route according to physicians. Collaborations Pharmaceuticals, Inc (CPI) now proposes in this Phase II SBIR to file a preIND (with the assistance of RTI International and Foresight Biosciences), perform manufacturing of PPT1 (with the assistance of Goodwin Biotechnology, Inc. and CMC consultant Dr. Stefan Proniuk), conduct rat and dog IND enabling toxicology studies (with the assistance of Charles River Laboratories) and ultimately filing an IND (with the assistance of RTI International and Foresight Biosciences). We will hire these experienced consultants and clinical research organizations to assist us throughout the process as they have years of experience. These collaborations will enable us to cost effectively and more rapidly translate this potential treatment to the clinic that can potentially save the lives of children living with this devastating disease. We have already obtained an Orphan Drug Designation and rare pediatric disease designation from the FDA for rhPPT1 as a biological product for a “rare pediatric disease” which offers several benefits in future upon FDA approval, including marketing exclusivity for 7 years and the potential to obtain a rare pediatric disease voucher and thus provide a return on investment (current value ~$100 M). We are engaged with CLN1 families communicating with them frequently to provide progress updates and we are now well positioned to continue the development of this potential treatment for a devastating disease. There is an important role to bring treatments to patients with ultra-rare diseases as illustrated by other companies such as Biomarin and Ultragenyx. Our work on developing rhPPT1 as an ERT for CLN1 would position us well to work on further rare diseases in future and grow CPI.

概括神经元蜡样质脂褐素沉积症 (NCL) 是一组无法治愈的神经退行性贮积症主要影响儿童和年轻人的大脑和视网膜，导致痴呆、失明、癫痫、和过早死亡，患病率约为每百万人口 1.5 至 9 人（每 100,000 名活人中有 1.3 至 7 人）婴儿期发病的 CLN1 疾病是由 CLN1/PPT1 基因突变引起的，该基因编码溶酶体酶棕榈酰蛋白硫酯酶-1 (PPT1) 导致酶减少或缺失 CLN1 疾病通常在 6 至 24 个月大时出现，有 2-3 名儿童患有此病。每年都会确定一份表格，目前美国有 24 名已知患有 CLN1 的儿童，巴西有 11 名已知的儿童（可能有许多未确诊）目前除了姑息治疗和疾病外没有其他治疗方法。此前已有报道称，在 CHO 细胞中表达的人类重组 PPT1 (rhPPT1) 会发生修饰。 PPT1 缺陷小鼠单次鞘内 (IT) 和静脉内 (IV) 给药后的疾病表型 (Ppt1-/-) 在成功完成第一阶段 SBIR 后，我们达到或超过了 IT 里程碑，我们对脑室内（ICV）以及联合给药途径进行了比较。每月通过 ICV 施用 rhPPT1 对 Ppt1-/- 小鼠产生了统计学上显着的治疗效果，例如由于拯救了超过 60% 的 PPT1 酶活性，降低了次级酶水平，减少了大脑和脊髓所有区域的神经元以及改善的步态和旋转结果也说明了这一点。单独通过这种途径输送酶可能就足够了，而不是与 IT 给药结合使用。现在已经使用 CHO-DG44 开发了我们自己的 PPT1 细胞系，该细胞系可扩展用于 GMP 生产和执行了初步纯化开发策略，我们正在开发 CLN1 的诊断工具。 CLN1 ERT 数据清楚地表明 ICV 剂量是未来研究的理想选择，这也是首选途径 Collaborations Pharmaceuticals, Inc (CPI) 现在建议在此 II 期 SBIR 中提交 preIND。（在 RTI International 和 Foresight Biosciences 的协助下），进行 PPT1 的制造（与在 Goodwin Biotechnology, Inc. 和 CMC 顾问 Stefan Proniuk 博士的协助下，进行大鼠和狗 IND 进行毒理学研究（在 Charles River Laboratories 的协助下）并最终提交 IND（与在 RTI International 和 Foresight Biosciences 的协助下）我们将聘请这些经验丰富的顾问和临床研究组织拥有多年的经验，可以在整个过程中为我们提供帮助。合作将使我们能够经济有效地、更迅速地将这种潜在的治疗方法转化为临床我们已经获得了一种可能挽救患有这种毁灭性疾病的儿童生命的方法。 rhPPT1 作为生物制品获得 FDA 孤儿药指定和罕见儿科疾病指定一种“罕见儿科疾病”，经 FDA 批准后将在未来带来多种好处，包括营销 7 年独家经营权，并有可能获得罕见儿科疾病优惠券，从而提供回报投资（当前价值约 1 亿美元）我们经常与 CLN1 家庭进行沟通。提供最新进展，我们现在已准备好继续开发这一潜力为极其罕见的患者提供治疗方法具有重要作用。 Biomarin 和 Ultragenyx 等其他公司所阐述的疾病，我们在开发 rhPPT1 方面的工作。作为 CLN1 的 ERT 将使我们能够在未来进一步研究罕见疾病并提高 CPI。