Antiviral Therapy for Human Rabies

Appolinário, Camila Michele; Jackson, Alan C.

doi:10.3851/imp2851

Cited by 45 publications

(45 citation statements)

References 84 publications

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“…Moreover, research on siRNAs targeting RABV essential genes has also gained a lot of potential in terms of delaying the process of RABV infection and allowing PEP to take effect. Recent progress on proper delivery systems has potentiated the future use of not only siRNA but also other therapeutic molecules such as small-molecule drugs [143] to cross the BBB for rabies treatment. Furthermore, a lot of interest has been focused on the development of monoclonal antibodies as potential alternatives for the limited and expansive RIG and, given the rapid advances in antibody engineering, it can be envisioned that in the near future some monoclonal antibodies would be licensed as adjuncts for RIG.…”

Section: Discussionmentioning

confidence: 99%

Rabies Control and Treatment: From Prophylaxis to Strategies with Curative Potential

Zhu

Guo

2016

Viruses

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Rabies is an acute, fatal, neurological disease that affects almost all kinds of mammals. Vaccination (using an inactivated rabies vaccine), combined with administration of rabies immune globulin, is the only approved, effective method for post-exposure prophylaxis against rabies in humans. In the search for novel rabies control and treatment strategies, live-attenuated viruses have recently emerged as a practical and promising approach for immunizing and controlling rabies. Unlike the conventional, inactivated rabies vaccine, live-attenuated viruses are genetically modified viruses that are able to replicate in an inoculated recipient without causing adverse effects, while still eliciting robust and effective immune responses against rabies virus infection. A number of viruses with an intrinsic capacity that could be used as putative candidates for live-attenuated rabies vaccine have been intensively evaluated for therapeutic purposes. Additional novel strategies, such as a monoclonal antibody-based approach, nucleic acid-based vaccines, or small interfering RNAs (siRNAs) interfering with virus replication, could further add to the arena of strategies to combat rabies. In this review, we highlight current advances in rabies therapy and discuss the role that they might have in the future of rabies treatment. Given the pronounced and complex impact of rabies on a patient, a combination of these novel modalities has the potential to achieve maximal anti-rabies efficacy, or may even have promising curative effects in the future. However, several hurdles regarding clinical safety considerations and public awareness should be overcome before these approaches can ultimately become clinically relevant therapies.

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Section: Discussionmentioning

confidence: 99%

Rabies Control and Treatment: From Prophylaxis to Strategies with Curative Potential

Zhu

Guo

2016

Viruses

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“…In addition to repurposing existing drugs, novel antiviral strategies have been explored for rabies. These have been reviewed extensively in the recent paper by Appolinario and Jackson [3] as well. In the following, we highlight some additional strategies.…”

Section: Novel Antiviralsmentioning

confidence: 99%

“…Current efforts and challenges in the discovery and development of rabies antivirals have recently been reviewed thoroughly [3]. Here we will briefly update this work on antivirals and further explore the efforts needed to find other, more potent anti-rabies molecules.…”

Section: Introductionmentioning

confidence: 99%

The path towards effective antivirals against rabies

Jochmans¹,

Neyts²

2019

Vaccine

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Rabies virus remains an important burden of disease claiming an estimated 60,000 lives each year, mainly children, and having a huge economical and societal cost. Post-exposure prophylaxis (PEP) is highly effective, however in patients that present with neurological symptoms the case-fatality ratio is extremely high (>99%). During the last decades several attempts to identify potent and effective antivirals were made. Only a few of these demonstrated improvement in clinical signs in animal studies and none of the trials in humans showed significant efficacy. Here we explore novel opportunities to identify more potent anti-rabies molecules. In particular important progress has been made on antivirals against other Mononegavirales (paramyxoviruses, filoviruses) which should be an impetus to test and optimize these molecules towards anti-rabies virus therapies. Effective rabies antivirals for therapeutic use need to be molecules that can be dosed into the cerebrospinal fluid and that rapidly and potently block ongoing virus replication and as such stop the further spread of the virus. Antivirals for prophylactic use can also be envisaged and these should be able to prevent infection of peripheral nerve cells and should have the potential to replace the current anti-rabies immunoglobulins that are used in PEP.

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“…Rabies is a vaccine-preventable infectious viral disease that damages the CNS of animals and humans. A post-exposure prophylaxis approved by World Health Organization involves the administration of rabies vaccine and immunoglobulin and is available to treat individuals exposed to RABV, but it must be administered before the clinical onset (Appolinario and Jackson, 2015;Rupprecht and Gibbons, 2004). Despite a few reported cases of individuals surviving symptomatic rabies, including one case that was treated with the Milwaukee Protocol (Jackson, 2013), it is extremely challenging to treat symptomatic patients.…”

Section: Introductionmentioning

confidence: 99%

“…Only two nucleoside analogs have been sufficiently investigated for their anti-RABV effect. Ribavirin, a broad-spectrum guanine nucleoside analog, inhibited RABV replication in vitro but failed to demonstrate a protective efficacy in human clinical cases (Appolinario and Jackson, 2015;Bussereau et al, 1988;Warrell et al, 1989). Favipiravir (T-705), the other nucleoside analog, exhibited potency as a rabies post-exposure prophylaxis in a mouse model (Yamada et al, 2016), suggesting that nucleoside analogs could act as potential anti-RABV agents.…”

Section: Introductionmentioning

confidence: 99%

Ribavirin-related compounds exert in vitro inhibitory effects toward rabies virus

et al. 2018

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Rabies remains an invariably fatal neurological disease despite the availability of a preventive vaccination and post-exposure prophylaxis that must be immediately administered to the exposed individual before symptom onset. There is no effective medication for treatment during the symptomatic phase. Ribavirin, a guanine nucleoside analog, is a potent inhibitor of rabies virus (RABV) replication in vitro but lacks clinical efficacy. Therefore, we attempted to identify potential ribavirin analogs with comparable or superior anti-RABV activity. Antiviral activity and cytotoxicity of the compounds were initially examined in human neuroblastoma cells. Among the tested compounds, two exhibited a 5- to 27-fold higher anti-RABV activity than ribavirin. Examination of the anti-RABV mechanisms of action of the compounds using time-of-addition and minigenome assays revealed that they inhibited viral genome replication and transcription. Addition of exogenous guanosine to RABV-infected cells diminished the antiviral activity of the compounds, suggesting that they are involved in guanosine triphosphate (GTP) pool depletion by inhibiting inosine monophosphate dehydrogenase (IMPDH). Taken together, our findings underline the potency of nucleoside analogs as a class of antiviral compounds for the development of novel agents against RABV.

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Antiviral Therapy for Human Rabies

Cited by 45 publications

References 84 publications

Rabies Control and Treatment: From Prophylaxis to Strategies with Curative Potential

Rabies Control and Treatment: From Prophylaxis to Strategies with Curative Potential

The path towards effective antivirals against rabies

Ribavirin-related compounds exert in vitro inhibitory effects toward rabies virus

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