SKELETAL MUSCLE-SPECIFIC IMMUNOTOXIN FOR THE TREATMENT OF FOCAL MUSCLE SPASM

Intramuscular injection of botulinum toxin type A (BTX) is used to tre at many disorders characterized by muscular spasms. The utility of BTX , however, is limited by its short duration of action, the development of resistance after repeated injections, and cross-reactivity with au tonomic neurons. To overcome these limitations, we engineered an immun otoxin (ITX) to damage skeletal muscle fibers selectively by chemicall y linking a monoclonal antibody against the nicotinic acetylcholine re ceptor to the toxin ricin. In vitro, the ITX was 20,000-fold more toxi c to myotubes than myoblasts, consistent with the degree of acetylchol ine receptor expression. The gastrocnemius muscles of 30 rats were uni laterally injected with a series of protein toxins at various concentr ations and examined histopathologically 7 and 30 days later. ITX produ ced destructive myopathic changes at a dose 300-fold less than the max imum tolerated dose. Assessment of rat muscle strength after unilatera l gastrocnemius injections showed that ITX was more effective and had a longer duration of action than BTX. ITXs may have potential for the treatment of involuntary muscle spasms.