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.

Public Health Relevance

All FDA-approved Botulinum neurotoxin (BoNT) products include a black box warning about serious adverse events and treatment-related deaths. Off-label use of BoNT to treat cerebral palsy (CP) associated spasticity is the condition that has most commonly resulted in death. Many CP patients still seek BoNT treatment to prevent lifelong-disabling deformities, despites warnings and dosage uncertainties. CytoDel has developed methods to bioengineer BoNT, and has identified Cyto-012 as its lead candidate for a safer BoNT product to treat spasticity disorders of large muscle groups, including for children with CP, because of its 10-fold improved safety margin relative to current BoNT products.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
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Special Emphasis Panel (ZRG1)
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Morris, Jill A
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Cytodel, LLC
New York
United States
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Vazquez-Cintron, Edwin; Tenezaca, Luis; Angeles, Christopher et al. (2016) Pre-Clinical Study of a Novel Recombinant Botulinum Neurotoxin Derivative Engineered for Improved Safety. Sci Rep 6:30429