Recombinant Botulinum Neurotoxin for Treatment of Spastic Disorders

描述(申请人提供)：肉毒杆菌神经毒素(BONT)是Botox(R)(Allergan)等药品的活性成分，FDA已批准其用于治疗和美容适应症。由于其固有的毒性，治疗大肌肉群痉挛障碍所需的BONT剂量令人不安地接近毒性剂量范围。已有严重的不良事件和死亡报告，导致FDA在整个药物类别的标签中引入黑盒警告。由于目前所有的BONT产品都是由肉毒杆菌培养物生产的，它们具有相似的安全特性，无法使用现代分子生物学工具进行设计以提高性能。CytoDel已经授权纽约大学在NIH支持下开发的技术，该技术可以生产具有定制特性的重组BONT衍生品。重组BONT衍生物已被开发出来，以改善特定适应症的表现，并使目前未被批准用于WT BONT的适应症，如影响美国80万人的脑性瘫痪(CP)。脑性瘫痪是最常见的与BONT治疗相关的情况-与死亡相关。这种方法也可以使中风、脑损伤和患有严重痉挛障碍的多发性硬化症患者受益。Cyto012是CytoDel推出的更安全的BONT产品的主要候选者，它旨在降低使用大剂量BONT治疗痉挛障碍的风险。初步研究表明，Cyto012的毒性是100,000-比肉毒梭菌培养产生的BONT低1倍，因此，与目前可用的安全裕度相比，它的安全裕度提高了10倍 邦特产品。这项拟议的研究旨在使用研究BONT药理学的标准小鼠模型，直接比较Cyto012和wt BONT/A的安全性和有效性。来自拟议研究的数据将用于确定在更复杂的临床前研究中要评估的剂量范围。这项拟议的研究还将用于评估Cyto012的免疫原性。这些数据是与FDA安排富有成效的IND前会议所必需的。拟议研究的成功完成将提供原则证明数据，以支持Cyto012的商业开发，用于治疗大型肌肉群的痉挛，以及用于脑瘫儿童的儿科使用。

DESCRIPTION (provided by applicant): Botulinum neurotoxin (BoNT) is the active ingredient in pharmaceutical products like Botox(R) (Allergan), which FDA has approved for therapeutic and aesthetic indications. Because of its inherent toxicity, the dose of BoNT required to treat spasticity disorders in large muscle groups is uncomfortably close to the toxic dose range. Serious adverse events and death have been reported, leading the FDA to introduce a black box warning into labeling for the entire drug class. Because all current BoNT products are manufactured from Clostridium botulinum cultures, they have similar safety characteristics, and cannot be engineered for improved performance using the tools of modern molecular biology. CytoDel has licensed NYU technology developed with NIH support, which enables production of recombinant BoNT derivatives with customized properties. Recombinant BoNT derivatives have been developed to improve performance in specific indications and enable indications currently not approved for wt BoNT, such as cerebral palsy (CP), which affects 800,000 people in the US. CP is the condition most commonly associated with BoNT treatment----related death. This approach can also benefit patients with stroke, brain injury and multiple sclerosi who suffer from severe spasticity disorders. Cyto012 is CytoDel's lead candidate for a safer BoNT product, and it is intended to reduce the risk associated with using large doses of BoNT to treat spasticity disorders. Preliminary studies demonstrate that Cyto012 is 100,000----fold less toxic than BoNT produced from Clostridium botulinum cultures, and consequently, has a ten-fold improved safety margin relative to the currently available BoNT products. The proposed research is intended to directly compare the safety and effectiveness of Cyto012 and wt BoNT/A, using a standard mouse model for studying BoNT pharmacology. The data from the proposed studies will be used to define the dosage range to be evaluated in more complex preclinical studies. The proposed research will also be used to evaluate the immunogenic potential of Cyto012. These data are needed to schedule productive pre-IND meetings with FDA. Successful completion of the proposed studies will provide proof-of-principle data to support commercial development of Cyto012 for treatment of spasticity in large muscle groups, and for pediatric use in children with cerebrl palsy.