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

• 批准号: 10483470
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483470
• 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; Clinical trial protocol document; Clone Cells; Code; Collaborations; 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; Intravenous; Investments; Laboratories; Letters; Licensing; Life; Live Birth; Lysosomal Storage Diseases; Marketing; Measures; Medical Genetics; 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; Rivers; Role; Rotarod Performance Test; Route; Safety; Seizures; Small Business Innovation Research Grant; Spielmeyer-Vogt Disease; Spinal Cord; Supervision; Taxes; Testing; Therapeutics for Rare and Neglected Diseases; Toxic effect; Toxicology; Translating; Translations; United States National Institutes of Health; Update; Work; Writing; antibody detection; 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; neuron loss; neuropathology; phenotypic data; programs; thioesterase PPT1 gene product; treatment effect; voucher; young adult

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.

摘要 神经性蜡样脂褐素病(NCLS)是一组无法治愈的神经退行性储存疾病 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，流行率约为每百万人口1.5至9人(每10万人中有1.3至7人死亡 出生)。婴儿发病的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)导致酶的减少或缺失 活动。CLN1疾病通常出现在6到24个月大的婴儿，有2到3名儿童患有这种疾病 表格每年确认，目前在美国有24名患有CLN1的儿童，在巴西有11名(可能有很多 更多未确诊)。目前，除了姑息疗法和疾病之外，还没有其他可用的治疗方法。 是致命的。在CHO细胞中表达的人重组PPT1(RhPPT1)先前已被报道修饰 单次鞘内注射和静脉注射PPT1基因缺陷小鼠的疾病表型 (Ppt1-/-)。在我们成功完成第一阶段SBIR后，我们达到或超过了我们的里程碑IT， 比较脑室注射(Icv)和联合给药途径。我们证明了这一点 每月经侧脑室注射重组人PPT1对Ppt1-/-小鼠产生显著的治疗效果，例如 由于挽救了60%以上的PPT1酶活性，降低了次生酶水平，减少了损失 大脑和脊髓所有区域的神经元和改善步态和旋转棒的结果。这也说明了 单独通过这种途径传递酶可能就足够了，而不是与IT剂量一起使用。我们 我们现在已经开发了我们自己的使用CHO-DG44的PPT1细胞系，它可以扩展到GMP生产和 实施了初步的纯化开发战略，我们正在开发CLN1的诊断工具。这个 CLN1 ERT数据清楚地表明，ICV给药是未来研究的理想选择，这也是一种首选路线 敬内科医生。Collaborations PharmPharmticals，Inc.(CPI)现在建议在此第二阶段SBIR中提交预IND (在RTI International和Foresight Biosciences的协助下)，制造PPT1(与 Goodwin Biotech，Inc.和CMC顾问Stefan Proniuk博士的协助)，进行老鼠和狗行业 进行毒理学研究(在Charles River实验室的协助下)，并最终提交IND(与 RTI国际和展望生物科学公司的协助)。我们将聘请这些经验丰富的顾问，并 临床研究机构帮助我们在整个过程中，因为他们有多年的经验。这些 合作将使我们能够更具成本效益和更快地将这种潜在的治疗方法转化为临床 这可能会挽救患有这种毁灭性疾病的儿童的生命。我们已经得到了一份 FDA将重组人PPT1作为生物制品指定为孤儿药物和罕见儿科疾病 一种“罕见的儿科疾病”，在FDA批准后，未来将提供几种益处，包括营销 7年的专有权和获得罕见儿科疾病代金券的可能性，从而提供 投资(现值约1亿美元)。我们与CLN1家庭进行了频繁的沟通 提供最新进展，我们现在处于有利地位，可以继续开发这一潜力 对一种毁灭性疾病的治疗。给超罕见的患者带来治疗有重要的作用 像BioMarin和Ultragenyx这样的其他公司所展示的疾病。我们开发重组人PPT1的工作 作为CLN1的ERT，将使我们在未来研究更多罕见疾病和提高CPI方面处于有利地位。