Development of gene replacement therapy for Sanfilippo Syndrome Type C

C 型桑菲利波综合征的基因替代疗法的开发

基本信息

批准号：
10541309
负责人：
Srikanth Singamsetty
金额：
$ 149.56万
依托单位：
PHOENIX NEST, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541309
关键词：
15 year old 5 year old Acetyl Coenzyme A Acetyltransferase Adult Affect Age Age-Years Biochemical Biodistribution Biological Assay Biological Markers Blindness Capital Carbohydrates Cell Line Cessation of life Child Childhood Clinical Clinical Trials Collaborations Communication Consultations Data Defect Dementia Deterioration Development Development Plans Developmental Delay Disorders Discipline Disease Disease model Doctor of Philosophy Dose Dose-Limiting Evaluation Eye Family Feedback Funding Future Goals Health Healthcare Systems Heparitin Sulfate Histopathology Human Human Resources Hyperactivity Impaired cognition Individual Inherited Injections Intervention Investigational Drugs Investigational New Drug Application Investments Lead Legal patent Life Lysosomal Storage Diseases Mediation Medical Medical Records Medical center Membrane Metabolic Diseases Morphology Motor Skills Mucopolysaccharidoses Mucopolysaccharidosis III Mus Nerve Degeneration Neurodegenerative Disorders Neurologic Neurologic Symptoms New Drug Approvals Online Mendelian Inheritance In Man Orphan Drugs Pathologic Pathology Patients Pharmacology Phase Phase I Clinical Trials Photoreceptors Physical therapy Plasmids Population Prevalence Problem behavior Process Proteins Proteoglycan Publishing Rare Diseases Rattus Recommendation Retina Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Risk Rivers Route Safety Small Business Innovation Research Grant Spain Supportive care Symptoms Synapses System Testing Texas Therapeutic Tissues Toxic effect Toxicokinetics Toxicology Translating United States Universities Visceral Visual Walking Wood material base behavior test behavioral phenotyping cognitive testing density early onset enzyme activity enzyme deficiency enzyme replacement therapy experience experimental group gene replacement therapy gene therapy gene therapy clinical trial immunogenicity improved in vivo manufacturing process manufacturing scale-up neuroinflammation preclinical development preservation product development professor reduce symptoms safety assessment safety testing scale up socioeconomics vector

项目摘要

PROJECT SUMMARY/ABSTRACT Lysosomal storage diseases (LSD) are rare inherited metabolic disorders caused by defects in the cellular catabolic system. Mucopolysaccharidosis Type IIIC (MPS IIIC or Sanfilippo disease type C) is one such LSD that is caused by deficiency of the enzyme heparan sulfate acetyl CoA: -glucosaminide N-acetyltransferase, (HGSNAT) essential for degradation of heparan sulfate, a repeating carbohydrate generally found attached to proteoglycans. This disease causes accumulation of heparan sulfate resulting in a progressive and severe neurological deterioration early in life with little somatic features. The symptoms in patients with MPS IIIC may present at an average age of 3.5 years of age with psychomotor developmental delays and behavioral problems. Before the age of 15 years verbal communication is often lost in patients with MPS IIIC. Most lose the ability to walk between the 20 and 30 years of age. The condition is fatal by an average age of 34 years (range, 25-48). Enzyme replacement therapies are not an option since the protein is localized and bound to lysosomal membrane. There are currently no treatments available for treatment of MPS IIIC. Individuals affected by MPS IIIC are managed with supportive care, consultation with medical professionals from multiple disciplines, physical therapy, and pharmacological interventions to alleviate symptoms. Gene therapy represents a reasonable and promising approach to provide a meaningful and long-term therapeutic benefit for this population in the near future. The goal of this SBIR project is to complete tissue level assessments in the disease model, scale up manufacturing and establish safety on a GLP regulated study in rats. These activities will help build a robust briefing package for IND-filing for our gene therapy product, JLK-247. The progress will help us navigate the “valley of death” by establishing milestones and making go/no-go decisions. The safe therapeutic dose-range established will help us extrapolate and translate therapeutic doses to clinical phase I trials. This proposal leverages the scientific expertise in gene therapy preclinical development and regulatory experience of Srikanth Singamsetty, PhD (Phoenix Nest, Inc.) for the product development. Jill Wood, BS (Phoenix Nest, Inc.), will manage the project finances and personnel responsible. Professor Steven Gray, PhD (The University of Texas Southwestern Medical Center, Dallas, TX) is our gene therapy subject matter expert. Successful completion of this project will help with initiating clinical trial dosing, a first step towards a long-term therapy for MPSIIC, a dreadful and fatal pediatric disease.

项目概要/摘要溶酶体贮积病（LSD）是一种罕见的遗传性代谢性疾病，由细胞缺陷引起 IIIC 型粘多糖贮积症（MPS IIIC 或 C 型 Sanfilippo 病）就是这样一种 LSD。这是由于硫酸乙酰肝素乙酰辅酶A缺乏引起的：α-氨基葡萄糖N-乙酰转移酶，（HGSNAT）对于硫酸乙酰肝素的降解至关重要，硫酸乙酰肝素是一种通常附着在这种疾病会导致硫酸乙酰肝素的积累，导致进行性和严重的症状。 MPS IIIC 患者可能会在生命早期出现神经功能恶化，但几乎没有躯体特征。平均年龄为 3.5 岁，患有精神运动发育迟缓和行为问题。 MPS IIIC 患者在 15 岁之前通常会丧失语言交流能力，大多数患者丧失语言交流能力。在 20 岁至 30 岁之间行走，平均年龄为 34 岁（范围：25-48 岁）。酶替代疗法不是一种选择，因为蛋白质是局部的并与溶酶体结合目前尚无治疗 MPS IIIC 患者的方法。 MPS IIIC 通过支持性护理、与来自多个学科的医疗专业人员的咨询进行管理，物理治疗和药物干预是缓解症状的代表。合理且有前景的方法可为该人群提供有意义且长期的治疗益处在不久的将来。该SBIR项目的目标是完成疾病模型中的组织水平评估，扩大规模生产和建立 GLP 规范的大鼠研究的安全性这些活动将有助于建立一个稳健的基础。我们的基因治疗产品 JLK-247 的 IND 申请简报包将帮助我们应对这一挑战。通过建立里程碑并做出继续/不继续的决定来“死亡之谷”。建立的方法将帮助我们推断治疗剂量并将其转化为临床 I 期试验。该提案利用了基因治疗临床前开发和监管方面的科学专业知识 Srikanth Singamsetty 博士（Phoenix Nest, Inc.）的产品开发经验 Jill Wood，BS。（Phoenix Nest, Inc.）将管理该项目的财务和负责人员。（德克萨斯大学西南医学中心，德克萨斯州达拉斯）是我们的基因治疗主题专家。该项目的成功完成将有助于启动临床试验剂量，这是迈向长期治疗的第一步。 MPSIIC 是一种可怕且致命的儿科疾病。