Recombinant Botulinum Neurotoxin for Treatment of Spastic Disorders

用于治疗痉挛性疾病的重组肉毒杆菌神经毒素

• 批准号: 8779301
• 负责人: PHILIP Arthur BAND
• 金额: $ 22.39万
• 依托单位: CYTODEL, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8779301
• 关键词: Address; Affect; Affinity Chromatography; Amino Acid Substitution; Animal Model; Animals; Biological; Biological Assay; Biomedical Engineering; Blinded; Bontoxilysin; Botox; Botulinum Toxin Type A; Boxing; Brain Injuries; Cells; Cerebral Palsy; Cessation of life; Characteristics; Chemistry; Child; Childhood; Cleaved cell; Clinical; Clostridium botulinum; Complex; Cytosol; Data; Deformity; Development; Disease; Dose; Drug Delivery Systems; Drug Formulations; Effectiveness; Engineering; Enzyme-Linked Immunosorbent Assay; Esthetics; Exhibits; FDA approved; Face; Genetic; Goals; In Vitro; Injection of therapeutic agent; Intramuscular Injections; Label; Lead; Legal patent; Length; Lethal Dose 50; Libraries; Licensing; Marketing; Methods; Molecular Biology; Motor Neurons; Multiple Sclerosis; Mus; Muscle; National Institute of Allergy and Infectious Disease; Neuromuscular Diseases; Neurons; Paralysed; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Preclinical Testing; Preparation; Production; Property; Recombinants; Relative (related person); Reporting; Research; Rights; Risk; S-nitro-N-acetylpenicillamine; Safety; Schedule; Serious Adverse Event; Serum; Side; Source; Spastic; Stroke; System; Technology; Testing; Therapeutic; Toxic effect; Uncertainty; United States National Institutes of Health; base; biodefense; commercial application; design; digital; disability; dosage; immunogenic; immunogenicity; improved; meetings; mouse model; neuromuscular activity; neutralizing antibody; novel; preclinical study; prevent; public health relevance; response; stability testing; success; tool

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.

描述（由申请人提供）：肉毒杆菌神经毒素（BoNT）是肉毒杆菌（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。 严重的不良事件和死亡已经报告，导致FDA在整个药物类别的标签中引入黑框警告。 由于目前所有的BoNT产品都是从肉毒梭菌培养物中生产的，它们具有相似的安全特性，并且不能使用现代分子生物学的工具进行工程改造以提高性能。 CytoDel已授权纽约大学在NIH支持下开发的技术，该技术能够生产具有定制特性的重组BoNT衍生物。 重组BoNT衍生物已被开发用于改善特定适应症的性能，并使目前尚未批准的wt BoNT适应症成为可能，例如在美国影响80万人的脑瘫（CP）。 CP是最常见的与BoNT治疗相关的疾病-相关死亡。 这种方法也可以使患有中风、脑损伤和多发性硬化的严重痉挛性疾病的患者受益。Cyto 012是CytoDel的一种更安全的BoNT产品的主要候选药物，它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，Cyto 012的毒性比从肉毒梭菌培养物产生的BoNT低100，000倍，因此，相对于目前可用的BoNT，Cyto 012具有10倍的安全裕度。 BoNT产品。 该研究旨在使用标准小鼠模型研究BoNT药理学，直接比较Cyto 012和wt BoNT/A的安全性和有效性。拟定研究的数据将用于确定在更复杂的临床前研究中评价的剂量范围。 拟议的研究还将用于评估Cyto 012的免疫原性潜力。 需要这些数据来安排与FDA的富有成效的IND前会议。拟议研究的成功完成将提供原理验证数据，以支持Cyto 012用于治疗大肌肉群痉挛和用于脑瘫儿童的商业开发。