Recombinant botulinum toxin with improved safety and effectiveness for treatment of dystonia

摘要 肉毒杆菌神经毒素(BoNT)是科学界已知的毒性最强的蛋白质。它也是中草药中的活性成分 ® 像肉毒杆菌(Allergan)这样的药物，已被证明对多种神经肌肉疾病安全有效 有迹象表明。目前所有的BONT产品都是由肉毒杆菌培养物生产的，并具有类似的 安全特性，包括剂量限制和标签中的黑盒警告。因为它的 固有的毒性和狭窄的治疗窗口，在适应症中很难达到最佳的临床结果 涉及大型肌肉群，如颈肌张力障碍、中风后痉挛和儿童脑性瘫痪。 虽然肌肉张力的改善是明显可以实现的，但临床医生倾向于谨慎地服用，总体来说 临床结果留下了很大的改进空间。在此，我们建议在使用 之前的“安全BONT”候选药物(SBIR阶段1 1R41NS086115-01A1)发现 对BONT/A1进行特定的氨基酸替换可以产生安全性更高的重组BONT/A1 利润率与重量/A1相比，(8,865,186美元)。最初设计和测试的领先候选者Cyto-012具有 提高了安全边际，但其绝对效力如此之大，疗效所需的剂量也 免疫原性。在这里，我们建议测试一种名为Cyto-014的新的重组BONT/A1衍生物，旨在 具有与wt bont/a1相似的效力和免疫原性，同时在安全性方面保持预期的改进 由我们的初步研究建议。这项建议旨在比较剂量-反应行为、安全性 在适当的动力研究中，Cyto-014相对于wt Bont/A1的边际和最大耐受量，以及 评价其免疫原性和重复治疗效果。圆满完成拟议中的 研究将支持第二阶段研究，重点放在旨在提交IND的临床前开发活动上。

Abstract Botulinum neurotoxin (BoNT) is the most toxic protein known to science. It is also the active ingredient in ® pharmaceutical products like Botox (Allergan), which have proven safe and effective for multiple neuromuscular indications. All current BoNT products are manufactured from Clostridium botulinum cultures and have similar safety characteristics, which include limitations on dosing and a black box warning in labeling. Because of its inherent toxicity and narrow therapeutic window, optimal clinical outcomes are difficult to achieve in indications involving large muscle groups, such as cervical dystonia, post-stroke spasticity and pediatric cerebral palsy. Though improved muscle tone can clearly be achieved, clinicians tend to dose on the side of caution, and overall clinical outcomes leave significant room for improvement. We here propose building on data generated with a previous candidate for a “safer BoNT” pharmaceutical (SBIR Phase 1 1R41NS086115-01A1) which found that specific amino acid substitutions to BoNT/A1 can produce a recombinant BoNT/A1 with an improved safety margin compared to wt BoNT/A1, (US 8,865,186). The initial lead candidate designed and tested, Cyto-012, had an improved safety margin, but its absolute potency was such that doses required for efficacy were also immunogenic. Here, we propose testing a new recombinant BoNT/A1 derivative termed Cyto-014, designed to have potency and immunogenicity similar to wt BoNT/A1, while retaining the desired improvement in safety suggested by our Preliminary Studies. This proposal is intended to compare the dose-response behavior, safety margin and maximum tolerated dose of Cyto-014 relative to wt BoNT/A1 in appropriately powered studies, and to evaluate its immunogenicity and effectiveness for repeat treatment. Successful completion of the proposed studies will support a Phase II study to focus on pre-clinical development activities aimed at filing an IND.