Development of Gene Replacement Therapy for Sanfilippo Syndrome Type C

C 型 Sanfilippo 综合征基因替代疗法的开发

基本信息

批准号：
10706562
负责人：
Srikanth Singamsetty
金额：
$ 149.49万
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/10706562
关键词：
15 year old 5 year old Acetyl Coenzyme A Acetyltransferase Adult Affect Age Age Years Binding 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 Healthcare Systems Heparitin Sulfate Histopathology Human Human Resources Hyperactivity Immobilization 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 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 Route Safety Small Business Innovation Research Grant Spain Supportive care Symptoms Synapses System Testing Texas Therapeutic Tissues Toxic effect Toxicokinetics Toxicology Transfection Translating United States Universities Visceral Visual Walking Wood material behavior test behavioral phenotyping cognitive testing commercialization density early onset economic impact enzyme activity enzyme deficiency enzyme replacement therapy experience experimental group gene replacement therapy gene therapy gene therapy clinical trial health economics immunogenicity improved in vivo manufacture manufacturing process manufacturing scale-up neuroinflammation pharmacologic preclinical development preservation product development professor reduce symptoms safety assessment safety testing scale up socioeconomics vector verbal

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.

项目摘要/摘要溶酶体储存疾病（LSD）是由细胞中缺陷引起的罕见遗传代谢性疾病分解代谢系统。 IIIC型粘二糖（MPS IIIC或Sanfilippo疾病C型）就是这样的LSD 这是由于乙酰硫酸乙二醇乙二醇COA的缺乏而引起的：-葡萄糖酰胺N-乙酰转移酶，（HGSNAT）对于硫酸乙酰肝素降解至关重要的，一种重复的碳水合物通常附着在蛋白聚糖。这种疾病会导致硫酸乙酰肝素的积累，导致进行性和严重生命早期的神经系统恶化，几乎没有躯体特征。 MPS IIIC患者的症状可能平均年龄3.5岁，患有精神运动的发育延迟和行为问题。 MPS IIIC患者经常丢失15岁之前的口头交流。大多数失去能力在20至30岁之间行走。该病情的平均年龄为34岁（范围为25-48）。酶替代疗法不是一种选择膜。目前尚无治疗MPS IIIC治疗的治疗方法。受到影响的个人 MPS IIIC通过支持性护理进行管理，与来自多个学科的医学专业人员进行磋商，物理疗法和药物干预措施以减轻症状。基因疗法代表合理而有希望的方法为该人群提供有意义的长期治疗益处在不久的将来。这个SBIR项目的目的是完成疾病模型中的组织水平评估，扩大规模在大鼠的GLP监管研究中制造并建立安全性。这些活动将有助于建立强大的用于我们基因治疗产品的IND申请的简报包JLK-247。进度将帮助我们导航通过建立里程碑并做出/不执行决定，“死亡谷”。安全的热剂量范围建立的将有助于我们推断并将治疗剂量转化为I期临床试验。该建议利用基因疗法临床前开发和调节的科学专业知识 Srikanth Singamsetty博士（Phoenix Nest，Inc。）的经验。吉尔·伍德（Jill Wood），学士学位（Phoenix Nest，Inc。）将管理负责项目财务和人员。史蒂文·格雷教授，博士（德克萨斯州达拉斯，德克萨斯大学西南医学中心）是我们的基因治疗主题专家。该项目的成功完成将有助于开始临床试验，这是长期迈向的第一步治疗MPSIIC，一种可怕的致命小儿疾病。