Introduction

The development of botulinum toxin for therapeutic use is marked by its cross-disciplinary use for varied medical conditions. In particular, botulinum toxin has become a valuable therapy for selected disorders, treated by multiple specialists, whereby symptoms were inadequately managed with existing treatments.

In this chapter, we provide an overview of development events, interspersed with personal observations of historical and human interest. Due to the structure and format of this book, this chapter is not fully referenced. For full reference citations to the events described here, the reader is referred to the additional reading list at the end of this document and the references therein and is encouraged to seek supplementary sources.

Currently unapproved uses are mentioned for historical purposes, and health care providers should ascertain product licensure information regarding locally approved indications. In describing the formally developed uses of botulinum toxin, we confine ourselves to those for which Botox^® (onabotulinumtoxinA) has been approved by regulatory agencies in the United States or Europe.

Identification, isolation, and characterization

The first well-described cases of medical illness after oral ingestion of an apparent foodstuff that may have contained some botulinum toxin were reported between 1817 and 1822 by the German physician Justinus Kerner. Kerner noted that the active substance interrupted signals from the motor nerves to muscles, but spared sensory nerves and cognitive abilities. He also theorized that the substance could possibly be used as therapy for medical conditions when ingested orally.

The bacterial etiology of botulism was first noted by the microbiologist Emile Pierre van Ermengen who documented his findings in 1897, identifying and naming the responsible bacteria as Bacillus botulinus, which later became Clostridium botulinum. In 1905, Tchitchikine found that C. botulinum produced a substance that affected neurotransmitter function. In 1919, Professor Burke of Stanford University described an alphabetical classification for the different serotypes of botulinum toxin based on his toxin–antitoxin experiments.

Purification and crystallization of botulinum neurotoxin followed in the ensuing decades, eventually enabling mechanism of action studies. Dr Carl Lamanna and colleagues observed dissociation between the hemagglutinating activity of botulinum toxin type A and its toxicity, leading to further studies that identified both toxic and non-toxic proteins in the crystalline toxin complex. Lamanna also observed the extreme potency of botulinum toxin, which would later be recognized as a major advantage for a local, injectable therapy. In the late 1940s and early 1950s, Arnold Burgen and Vernon Brooks at McGill University discovered that botulinum toxin acted presynaptically to block the release of acetylcholine from motor nerve terminals. Brooks mentioned to a colleague, Edward Schantz, that the toxin might be useful for weakening hyperactive muscles.

Edward Schantz had worked in the Chemical Corps at Fort Detrick purifying botulinum toxin using the method established by Lamanna and Duff. Schantz then relocated to the University of Wisconsin where he perfected the purification and crystallization of botulinum toxin. In 1971, Daniel Drachman, with toxin purified and supplied by Edward Schantz, showed that injecting minute amounts of botulinum toxin type A in the hindlimbs of chicks caused local denervation. In 1979, Lance Simpson described the key elements of the mechanism of action: binding, internalization, translocation, and interruption of neurotransmitter release. Pamphlett clarified that there is neither cell death nor axonal degeneration and the affected nerve terminals do not degenerate. Although traditionally called a neurotoxin because of its potential to cause generalized muscle weakness at exceedingly high doses, in 2004 our group reported that botulinum toxin type A is not cytotoxic.

Exploration of clinical potential

In the 1960s and 1970s, Alan Scott, an ophthalmologist in San Francisco, was seeking an alternative to surgery for the correction of strabismus. Scott has described the events that led to his clinical studies with botulinum toxin type A in several articles, and readers are encouraged to read his accounts. Scott and his colleague Carter Collins were studying the forces and actions of eye muscles, and they considered whether a long-acting muscle-weakening agent could be used for treatment of strabismus. Based on Daniel Drachman’s work, Scott thought that botulinum toxin might be an option. Drachman directed Scott to Edward Schantz, who provided him with botulinum toxin for testing. It was noted that, historically, outbreaks of type A botulism produced predominantly motor weakness, whereas type B caused a predominance of autonomic symptoms and thus type A was selected by Scott. Schantz provided the crystallized botulinum toxin type A by regular mail in a metal tube placed in another metal tube.

Scott took the crystalline toxin into his laboratory and diluted it into small aliquots, buffered it with albumin instead of gelatin, and developed testing and storage conditions. He found that injecting minute amounts into extraocular muscles of monkeys with electromyographic (EMG) guidance produced long-lasting effects for the correction of strabismus and, at the doses used, without any systemic effects. Scott published these preclinical results in 1973, performed additional preclinical toxicology studies to evaluate doses that produced systemic effects in primates and obtained an Investigational New Drug (IND) designation from the US Food and Drug Administration (FDA) to conduct the first clinical trial for humans with strabismus in 1977 by injecting minute amounts locally into the extraocular muscles. He called his formulation ‘Oculinum’ (Fig. 2.1). This clinical trial led to the 1980 publication of the first 19 patients, where efficacy in treating strabismus was reported.

Figure 2.1 Oculinum 100 units research vial.

In the early 1980s, at the Columbia University Neurological Institute, we were funded by the Dystonia Medical Research Foundation with the primary goal of identifying effective treatments for dystonia, in addition to exploring the disease’s genetic underpinnings. Stanley Fahn was the principal investigator of the Center, Mitchell Brin was a Movement Disorders Fellow and Center’s Program Coordinator, and Andrew Blitzer was acting Chairman of the Department of Otolaryngology. Dr Fahn learned directly from Dr Scott when he attended a workshop in which Dr Scott described his use of Oculinum. He submitted a protocol to the Columbia University Institutional Review Board and also obtained an IND from the FDA to evaluate the potential therapeutic use of Oculinum. The clinical protocol’s inclusion criteria enabled our broad research program.