Skeletal muscle-specific immunotoxin for the treatment of focal muscle spasm.
Intramuscular injection of botulinum toxin type A (BTX) is used to treat 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 autonomic neurons. To overcome these limitations, we engineered an immunotoxin (ITX) to damage skeletal muscle fibers selectively by chemically linking a monoclonal antibody against the nicotinic acetylcholine receptor to the toxin ricin. In vitro, the ITX was 20,000-fold more toxic to myotubes than myoblasts, consistent with the degree of acetylcholine receptor expression. The gastrocnemius muscles of 30 rats were unilaterally injected with a series of protein toxins at various concentrations and examined histopathologically 7 and 30 days later. ITX produced destructive myopathic changes at a dose 300-fold less than the maximum tolerated dose. Assessment of rat muscle strength after unilateral 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.
Hott
J S
JS
Biochemistry Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Dalakas
M C
MC
Sung
C
C
Hallett
M
M
Youle
R J
RJ
D000818:Animals; D000911:Antibodies, Monoclonal; D019274:Botulinum Toxins, Type A / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D000922:Immunotoxins / Q000627:therapeutic use* / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009124:Muscle Proteins / Q000096:biosynthesis; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D009135:Muscular Diseases / Q000188:drug therapy*; D015202:Protein Engineering; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000276:immunology; D012276:Ricin / Q000627:therapeutic use* / Q000633:toxicity*; D013035:Spasm / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D009124:Muscle Proteins; D011978:Receptors, Nicotinic; D012276:Ricin; D019274:Botulinum Toxins, Type A