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.

概括神经元粘膜脂蛋白（NCLS）是一组无法治愈的神经退行性储存障碍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，和早期死亡，患病率约为每百万人口约1.5至9人出生）。婴儿发作形式CLN1疾病是由CLN1/PPT1基因突变引起的，该基因编码为编码溶酶体酶棕榈酰蛋白硫酯酶1（PPT1）导致酶还原或不存在活动。 CLN1疾病通常会出现6至24个月大，有2-3名儿童每年确定的表格，目前在美国有24名CLN1的儿童，在巴西有11名（可能有很多除姑息治疗和疾病外，目前尚无治疗方法致命。以前已经报道了在CHO细胞中表达的人重组PPT1（RHPPT1） PPT1缺乏小鼠的单个鞘内（IT）和静脉内（IV）给药后的疾病表型（ppt1 - / - ）。成功完成了第I阶段SBIR之后，我们遇到或超过了里程碑，比较了脑室内（ICV）以及联合输送途径。我们证明了这一点通过ICV每月给予RHPPT1在PPT1 - / - 小鼠中产生统计学上显着的治疗效果，此类随着超过60％的PPT1酶活性的营救降低了继发酶水平，降低了损失大脑和脊髓所有区域的神经元以及步态和rotarod结果改善。这也说明了仅通过此路线递送酶就足够了，而不是与IT剂量结合使用。我们现在已经使用CHO-DG44开发了我们自己的PPT1细胞系，这对于GMP制造和执行了初始的纯化开发策略，我们正在为CLN1开发诊断工具。这 CLN1 ERT数据清楚地指出ICV剂量是未来研究的理想选择，这也是首选途径给医生。合作Pharmaceuticals，Inc（CPI）现在在此II阶段SBIR中提议提交预先用途（在RTI International和Foresight Biosciences的协助下）执行PPT1的制造（与 Goodwin Biotechnology，Inc。和CMC顾问Stefan Proniuk博士的协助，进行RAT和DOG IND 启用毒理学研究（在查尔斯河实验室的协助下），并最终提交IND（与 RTI国际和远见生物科学的协助）。我们将雇用这些经验丰富的顾问和临床研究组织将在整个过程中为我们提供帮助，因为他们拥有多年的经验。这些合作将使我们能够有效，更快地将这种潜在治疗转化为诊所这可能会挽救这种毁灭性疾病的儿童的生命。我们已经获得了 FDA作为生物产品的FDA的孤儿药物名称和罕见的小儿疾病设计对于“罕见的小儿疾病”，在FDA批准后将在未来带来一些好处，包括营销排他性7年，并有可能获得罕见的小儿疾病代金券，从而提供了回报投资（当前价值〜$ 100 m）。我们与CLN1家庭经常与他们交流为了提供进度更新，我们现在处于良好的位置，可以继续发展这种潜力治疗毁灭性疾病。为超鲁尔患者带来治疗有重要作用如Biomarin和Ultragenyx等其他公司所示的疾病。我们开发RHPPT1的工作作为CLN1的ERT，将来可以将我们的进一步罕见疾病努力并增加CPI。