Development of gene replacement therapy for Sanfilippo Syndrome Type C

项目总结/摘要 溶酶体贮积病（LSD）是一种罕见的遗传性代谢紊乱， 分解代谢系统粘多糖样变性IIIC型（MPS IIIC或Sanfilippo病C型）就是这样一种LSD 其由硫酸乙酰肝素乙酰辅酶A：β-氨基葡萄糖苷N-乙酰转移酶的缺乏引起， （HGSNAT）对于硫酸乙酰肝素的降解是必需的，硫酸乙酰肝素是一种重复的碳水化合物， 蛋白聚糖这种疾病引起硫酸乙酰肝素的积累，导致进行性和严重的 生命早期的神经系统退化，几乎没有躯体特征。MPS IIIC患者的症状可能 平均年龄为3.5岁，患有精神发育迟缓和行为问题。 在15岁之前，MPS IIIC患者经常失去语言交流。大多数人失去了 在20到30岁之间走路。这种情况是致命的平均年龄为34岁（范围，25-48）。 酶替代疗法不是一种选择，因为蛋白质是本地化的，并结合到溶酶体 膜的目前尚无治疗MPS IIIC的方法。受影响的个人 MPS IIIC通过支持性治疗进行管理，咨询多个学科的医学专业人员， 物理治疗和药物干预以缓解症状。基因治疗代表了 为该人群提供有意义的长期治疗获益的合理且有前景的方法 在近期 该SBIR项目的目标是在疾病模型中完成组织水平评估， 在大鼠中进行GLP监管研究，并确定其安全性。这些活动将有助于建立一个强大的 我们基因治疗产品JLK-247的IND申报简报包。这些进展将帮助我们 通过建立里程碑和做出去/不去的决定来实现“死亡之谷”。安全治疗剂量范围 这将帮助我们推断并将治疗剂量转化为临床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.）的经验为产品开发。Jill Wood，理学学士 （Phoenix Nest，Inc.），将负责管理项目的财务和人员。Steven Gray教授，博士 (The德克萨斯大学西南医学中心，达拉斯，TX）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，这是迈向长期的第一步。 MPSIIC是一种可怕而致命的儿科疾病。

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.