Targeting therapy to the neuromuscular junction: proof of concept.
Bottom Line: The site of pathology in myasthenia gravis (MG) is the neuromuscular junction (NMJ).A single-chain antibody directed against the alpha subunit of the acetylcholine receptor was synthesized (scFv-35) and coupled to decay-accelerating factor (DAF, scFv-35-DAF). scFv-35-DAF was tested in a passive model of experimentally acquired MG.We demonstrate a method to effectively target a therapeutic agent to the NMJ.
Affiliation: Department of Pharmacology and Physiology, George Washington University, Washington, DC, USA.Show MeSH
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Mentions: After 24 h of EAMG induction, PBS-treated and scFv-35–treated rats began to show weakness, which was not evident in the scFv-35-DAF–treated rats (Fig. 5). By 48 h, vehicle- and scFv-35–treated rats had become profoundly weak (clinical scores of 3.4 ± 0.55 and 3.4 ± 0.89, respectively) to the point of requiring euthanasia, whereas scFv-35-DAF–treated rats had developed only moderate weakness (clinical score of 2 ± 0, P < 0.01 compared with both scFv-35 and PBS; Fig. 5). All animals were then killed for histological analysis. Quantitative analysis of complement deposition demonstrated significantly less MAC deposition at endplates of scFv-35-DAF–treated animals (mean 1226 ± 610 pixel density) compared with both vehicle- and scFv-35–treated rats (mean 1611 ± 644 pixel density and 1979 ± 453 pixel density, respectively; P < 0.01 compared with scFv-DAF treated), whereas scFv-35–treated rats had a marginally higher degree of complement deposition compared with vehicle-treated rats (Fig. 6). Consistent with the better clinical outcome, AChR density was significantly greater in the scFv-35-DAF–treated rats (mean 3208 ± 953 pixel density) than scFv-35–treated and vehicle-treated rats (means 1489 ± 865 pixel density and 1128 ± 716 pixel density, respectively; P < 0.001 compared with scFv-35-DAF).
Affiliation: Department of Pharmacology and Physiology, George Washington University, Washington, DC, USA.