Genome editing and the next generation of antiviral therapy

Stone, Daniel; Niyonzima, Nixon; Jerome, Keith R.

doi:10.1007/s00439-016-1686-2

Cited by 42 publications

(33 citation statements)

References 104 publications

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“…Thus far, the history of oligonucleotide therapeutics shows that success hinges on proactive pursuit of robust evidence closely aligned with the so-called 5 pillars of drug discovery (Cook et al, 2014). The commercial demise of fomivirsen (Krieg, 2011), the safety ambivalence of mipomersen (Panta, Dahal, & Kunwar, 2015), the questionable efficacy of the splicing modulators drisapersen (Hodgkinson et al, 2016) and eteplirsen (Miceli & Nelson, 2016), and the phase II/III failures or commercial abandonment of synthetic and virus-expressed siRNA drugs (Quark Pharmaceuticals and Benitec BioPharma, respectively) has turned the focus onto technological alternatives such as gene-editing (Stone, Niyonzima, & Jerome, 2016) and in vitro transcribed RNA (Devoldere, Dewitte, De Smedt, & Remaut, 2016).…”

Section: Concluding Remarks and Future Challengesmentioning

confidence: 99%

Clinical potential of oligonucleotide-based therapeutics in the respiratory system

Moschos

Usher

Lindsay

2017

Pharmacology & Therapeutics

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The discovery of an ever-expanding plethora of coding and non-coding RNAs with nodal and causal roles in the regulation of lung physiology and disease is reinvigorating interest in the clinical utility of the oligonucleotide therapeutic class. This is strongly supported through recent advances in nucleic acids chemistry, synthetic oligonucleotide delivery and viral gene therapy that have succeeded in bringing to market at least three nucleic acid-based drugs. As a consequence, multiple new candidates such as RNA interference modulators, antisense, and splice switching compounds are now progressing through clinical evaluation. Here, manipulation of RNA for the treatment of lung disease is explored, with emphasis on robust pharmacological evidence aligned to the five pillars of drug development: exposure to the appropriate tissue, binding to the desired molecular target, evidence of the expected mode of action, activity in the relevant patient population and commercially viable value proposition.

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Section: Concluding Remarks and Future Challengesmentioning

confidence: 99%

Clinical potential of oligonucleotide-based therapeutics in the respiratory system

Moschos

Usher

Lindsay

2017

Pharmacology & Therapeutics

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“…To the extent that viral latency is evaluated only in dissected dorsal root ganglia, it is possible that important sites of latency could be missed. For example, the emergence of the fairly diffuse autonomic ganglia as an important reservoir of reactivating virus suggests that gene therapy directed only at the DRG is unlikely to be successful in eradicating all latent or reactivating virus (30). Similarly, antivirals designed to specifically target reactivation mechanisms in sensory neurons may not be effective in autonomic neurons.…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus 2 in Autonomic Ganglia: Evidence for Spontaneous Reactivation

Pieknik

Bertke

Krause

2019

J Virol

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Herpes simplex virus 2 (HSV-2) can be transmitted in the presence or absence of lesions, allowing efficient spread among the general population. Recurrent HSV genital lesions are thought to arise from reactivated latent virus in sensory cell bodies of the dorsal root ganglia (DRG). However, HSV-2 has also been found latent in autonomic ganglia. Spontaneous reactivation or a low level of chronic infection could theoretically also occur in these peripheral nervous tissues, contributing to the presence of infectious virus in the periphery and to viral transmission. Use of a recently described, optimized virus with a monomeric mNeonGreen protein fused to viral capsid protein 26 (VP26) permitted detection of reactivating virus in explanted ganglia and cryosections of DRG and the sacral sympathetic ganglia (SSG) from latently infected guinea pigs. Immediate early, early, and late gene expression were quantified by droplet digital reverse transcription-PCR (ddRT-PCR), providing further evidence of viral reactivation not only in the expected DRG but also in the sympathetic SSG. These findings indicate that viral reactivation from autonomic ganglia is a feature of latent viral infection and that these reactivations likely contribute to viral pathogenesis. IMPORTANCE HSV-2 is a ubiquitous important human pathogen that causes recurrent infections for the life of its host. We hypothesized that the autonomic ganglia have important roles in viral reactivation, and this study sought to determine whether this is correct in the clinically relevant guinea pig vaginal infection model. Our findings indicate that sympathetic ganglia are sources of reactivating virus, helping explain how the virus causes lifelong recurrent disease.

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“…Each of these technologies specifically recognize and locate a target sequence with homologous binding specific protein domains or the guide RNA (gRNA) and catalyze a DNA double stranded break by attached restriction enzyme and reviewed extensively in recent past (167). Because of the precision of programmable nucleases these technologies are proposed as a powerful antiviral therapy for persistent viral infections (168,169). Proof-of-concept studies have been performed to treat multiple disorders, including in vivo experiments in mammals and even early phase human trials (NCT01455389, NCT00595088, and NCT01118052).…”

Section: Hpv Genome Targeting Approachesmentioning

confidence: 99%

Therapeutic startegies for human papillomavirus infection and associated cancers

et al. 2018

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Human papillomavirus (HPV) infection is linked to development of cancer of cervix, vagina, vulva, penis, ano-genital and non-genital oro-pharyngeal sites. HPV being a sexually transmitted virus infects both genders equally but with higher chances of pathological outcome in women. In the absence of organized screening programs, women report HPV-infected lesions at relatively advanced stages where they are subjected to standard treatments that are not HPV-specific. HPV infection-driven lesions usually take 10-20 years for malignant progression and are preceded by well-characterized pre-cancer stages. Despite availability of window for pharmacological intervention, therapeutic that could eradicate HPV from infected lesions is currently lacking. A variety of experimental approaches have been made to address this lacuna and there has been significant progress in a number of lead molecules which are in different stages of clinical and pre-clinical development. Present review provides a brief overview of the magnitude of the problem and current status of research on promising lead molecules, formulations and therapeutic strategies that showed potential to translate to clinically-viable HPV therapeutics to counteract this reproductive health challenge.

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Genome editing and the next generation of antiviral therapy

Cited by 42 publications

References 104 publications

Clinical potential of oligonucleotide-based therapeutics in the respiratory system

Clinical potential of oligonucleotide-based therapeutics in the respiratory system

Herpes Simplex Virus 2 in Autonomic Ganglia: Evidence for Spontaneous Reactivation

Therapeutic startegies for human papillomavirus infection and associated cancers

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