Intracerebral transfection of anti-rabies virus antibodies is an effective therapy for rabies

Abstract

27Rabies is a zoonotic neurological disease with 100% lethality. Some of the rare human 28 patients who survived after multiple drug treatment have inherited severe sequelae. The 29 objective of this study was to investigate the action of the transfection of antibodies against 30 rabies in the central nervous system of mice as target therapy for rabies. 32Author summary 33 The present study showed that after 48 h of RABV inoculation, mice injected by the 34 intracerebral route with anti-RABV F(ab')₂ complexed with Bioporter® Protein Delivery 35 Reagent (Genlantis) as a transfection agent, showing a morbidity/mortality rate of 30% with a 36 minimum incubation period of seven days, while in the control group a significantly higher 37 (p<0.0198) 90% morbidity/mortality was reached in thirteen days after a maximum 5-day 38 incubation period, suggesting that the transfection of anti-RABV antibodies into the brain might 39 prevent or delay RABV dissemination in an early stage of rabies infection. For the first time, a 40 single compound was able to inhibit replication of the virus in the nervous system with high 41 efficiency. This result can provide important results for the planning of protocols to prevent the 42 fatal outcome of the disease in advanced stages. New studies focusing on the optimization of 43 intracellular antibody delivery may be one of the main bases for more effective anti-rabies 44 therapy. 45 46 47 48Rabies is a zoonotic neurological disease with 100% lethality; some of the few human 49 patients who survived after a multi-drug treatment developed severe motor impairment due to 50 ischaemic encephalopathy followed by necrosis of the hippocampus, cerebellum and cortex [1-51 2]. The use of immunomodulators and antivirals has not been shown to be effective in inhibiting 52 the progression of the disease when tested in mice and humans [3][4]. Circa 59,000 human 53 deaths occur worldwide yearly due to rabies, and although it is preventable with pre and post-54 exposure prophylaxis, the logistics and costs involved in rabies treatments are a limiting factor 55 to saving lives [5]. 56 Rabies lyssavirus RABV (Mononegavirales: Rhabdoviridae: Lyssavirus) is a 57 neurotropic virus with a circa 11 Kb negative-sense single-stranded RNA as a genome that 58 codes for the nucleoprotein (N), phosphoprotein (P), matrix protein (M), envelope glycoprotein 59 (G) and the RNA-dependent RNA-polymerase L protein [6], and it is most often transmitted 60 amongst mammals via saliva after an initial local replication in muscle cells that follows to the 61 central nervous system (CNS) via axons [7]. Within a variable period of time after infection, 62 signs of hyperactivity, hypersalivation and hydrophobia are detectable. The virus causes enough 63damage to the brain in a few days that the infection invariably leads to coma and death by 64 cardio-respiratory arrest [8]. 65 Here, we show that the use of intracerebral transfection of anti-RABV antibodies to treat 66 mice inoculated with RABV reduces mortality and extends t...

Intracerebral transfection of anti-rabies virus antibodies is an effective therapy for rabies

“…Prior to the Milwaukee Protocol, few human cases of rabies survival received post-exposure prophylaxis only with administration of the vaccine [15,16,17,18]. Complete recovery or with sequels in rabies patients is limited to a few cases in the literature linked to the history of immunization with the combination of vaccines and passive immunization of antibodies at the onset of symptoms [19,20,21]. Studies with B cell-deficient mice, which underwent CNS virus inhibition after peripheral .…”