Recombinant Botulinum Neurotoxin for Treatment of Spastic Disorders

描述（由申请人提供）：肉毒杆菌神经毒素（BoNT）是药物产品中的活性成分，如肉毒杆菌(R) (Allergan)， FDA已批准用于治疗和美容适应症。由于其固有的毒性，治疗大肌群痉挛障碍所需的BoNT剂量接近毒性剂量范围，令人不舒服。严重的不良事件和死亡已被报道，导致FDA在整个药物类别的标签上引入了黑框警告。由于目前所有的BoNT产品都是由肉毒杆菌培养物制造的，它们具有相似的安全特性，并且不能使用现代分子生物学工具进行改造以提高性能。CytoDel已获得美国国立卫生研究院支持下开发的NYU技术许可，该技术可生产具有定制特性的重组BoNT衍生物。重组BoNT衍生物已被开发出来，以改善特定适应症的疗效，并使目前尚未批准用于wt BoNT的适应症成为可能，例如脑瘫（CP），在美国影响着80万人。CP是BoNT治疗中最常见的疾病----相关死亡。这种方法也可以使中风、脑损伤和多发性硬化症患者受益，这些患者患有严重的痉挛性疾病。Cyto012是CytoDel的一种更安全的BoNT产品的主要候选产品，旨在降低使用大剂量BoNT治疗痉挛性疾病的风险。初步研究表明，与肉毒杆菌培养物产生的BoNT相比，Cyto012的毒性低100,000----倍，因此，相对于目前可用的安全边际提高了10倍

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.