A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis

Background: new drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. anti-onchocerca drug development is hampered by the lack of a facile model. we postulated that scid mice could be developed as a fmacrofilaricide screening model.methods: the filaricides: albendazole (abz),diethylcarbamazine (dec),flubendazole (fbz),ivermectin (ivm) and the anti-wolbachia macrofilaricide,minocycline (min) were tested in brugia malayi (bm)-parasitized balb/c scid mice vs vehicle control (vc). responses were compared to balb/c wild type (wt). onchocerca ochengi male worms or onchocercomata were surgically implanted into balb/c scid,cb.17 scid,balb/c wt mice or meriones gerbils. survival was evaluated at 7-15 days. balb/c scid were tested to evaluate the responsiveness of pre-clinical macrofilaricides fbz and rifapentine (rifap) against male onchocerca.results: wt and scid responded with >95% efficacy following abz or dec treatments against bm larvae (p < 0.0001). ivm was partially filaricidal against bm larvae in wt and scid (wt; 39.8%,p = 0.0356 and scid; 56.7%,p = 0.026). scid responded similarly to wt following ivm treatment of microfilaraemias (wt; 79%,p = 0.0194. scid; 76%,p = 0.0473). fbz induced a total macrofilaricidal response against adult bm in wt and scid (wt; p = 0.0067,scid; p = 0.0071). min induced a >90% reduction in bm wolbachia burdens (p < 0.0001) and a blockade of microfilarial release (p = 0.0215) in scid. male onchocerca survival was significantly higher in scid vs wt mice,but not gerbils,after +15 days (60% vs 22% vs 39% p = 0.0475). onchocercoma implants had engrafted into host tissues,with evidence of neovascularisation,after +7 days and yielded viable macro/microfilariae ex vivo. fbz induced a macrofilaricidal effect in onchocerca male implanted scid at +5 weeks (fbz; 1.67% vs vc; 43.81%,p = 0.0089). wolbachia loads within male onchocerca were reduced by 99% in implanted scid receiving rifap for +2 weeks.conclusions: we have developed a 'pan-filarial' small animal research model that is sufficiently robust,with adequate capacity and throughput,to screen existing and future pre-clinical candidate macrofilaricides. pilot data suggests a murine onchocercoma xenograft model is achievable.