Botulinum neurotoxin: history of clinical development

Abstract

The clinical development of botulinum neurotoxin began in the late 1960s with the search for an alternative to surgical realignment of strabismus. At that time, surgery of the extraocular muscles was the primary treatment for strabismus, but it was unsatisfactory for some patients because of the variability in results, consequent high reoperation rates and its invasive nature. In an attempt to find an alternative, Alan B. Scott, an ophthalmologist from the Smith–Kettlewell Eye Research Institute in San Francisco, investigated the effects of different compounds injected locally into the extraocular muscles to chemically weaken them. The drugs tested initially proved unreliable, short acting or necrotizing (Scott et al ., 1973). About this time, Scott became aware of Daniel Drachman, a renowned neuroscientist at Johns Hopkins University and his work, in which he had been injecting minute amounts of botulinum neurotoxin directly into the hind limbs of chickens to achieve local denervation (Drachman, 1964). Drachman introduced Scott to Edward Schantz (1908–2005), who was producing purified botulinum neurotoxins for experimental use and generously making them available to the academic community. Schantz himself credits Vernon Brooks with the idea that botulinum neurotoxin might be used for weakening muscle (Schantz, 1994). Brooks worked on the mechanism of action of botulinum toxin for his PhD under the mentorship of Arnold Burgen, who suggested the project to him (Brooks, 2001). Schantz had left the US Army Chemical Corps at Fort Detrick, Maryland, in 1972 to work at the Department of Microbiology and Toxicology, University of Wisconsin in Madison. Using acid precipitation purification techniques worked out at Fort Detrick by Lamanna and Duff, Schantz was able to make purified botulinum toxins.