siRNA rescues nonhuman primates from advanced Marburg and Ravn virus disease

Thi, Emily P.; Mire, Chad E.; Lee, Amy C.H.; Geisbert, Joan B.; Ursic-Bedoya, Raùl; Agans, Krystle N.; Robbins, Marjorie; Deer, Daniel J.; Cross, Robert W.; Kondratowicz, Andrew S.; Fenton, Karla A.; MacLachlan, Ian; Geisbert, Thomas W.

doi:10.1172/jci96185

Cited by 27 publications

(17 citation statements)

References 30 publications

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“…Therefore, the difference in disease and pathogenicity between these 2 macaque species offers an opportunity to study the underlying molecular determinants and decipher mechanisms involved in pathogenesis. However, the lack of severe disease and lethality after RAVV infection in rhesus macaques (in animals R1 and R2) is in contrast to published findings in which infection with a lower passage of RAVV caused uniform lethality in rhesus macaques [27,28]. The RAVV isolate used in our study shows a glycine-to-alanine change in the GP at position 393 (base pair 7118) (Supplementary Table 1).…”

Section: Discussioncontrasting

confidence: 85%

Distinct Biological Phenotypes of Marburg and Ravn Virus Infection in Macaques

Nicholas

Rosenke

Feldmann

et al. 2018

The Journal of Infectious Diseases

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Filoviruses are among the most pathogenic infectious agents known to human, with high destructive potential, as evidenced by the recent Ebola virus epidemic in West Africa. As members of the filovirus family, marburgviruses have caused similar devastating outbreaks, albeit with lower case numbers. In this study we compare the pathogenesis of Ravn virus (RAVV) and Marburg virus (MARV) strains Angola, Musoke, and Ozolin in rhesus and cynomolgus macaques, the 2 nonhuman primate species most commonly used in filovirus research. Our results reveal the most pathogenic MARV strain to be Angola, followed by Musoke, whereas Ozolin is the least pathogenic. We also demonstrate that RAVV is highly pathogenic in cynomolgus macaques but less pathogenic in rhesus macaques. Our results demonstrate a preferential infection of endothelial cells by MARVs; in addition, analysis of tissue samples suggests that lymphocyte and hepatocyte apoptosis might play a role in MARV pathogenicity. This information expands our knowledge about pathogenicity and virulence of marburgviruses.

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Section: Discussioncontrasting

confidence: 85%

Distinct Biological Phenotypes of Marburg and Ravn Virus Infection in Macaques

Nicholas

Rosenke

Feldmann

et al. 2018

The Journal of Infectious Diseases

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“…26 While these LNPs were initially developed for use with RNA interference (RNAi) components such as Onpattro, they can also be used for CRISPR/Cas delivery. 27…”

Section: Nonviral Delivery Methodsmentioning

confidence: 99%

Delivery Aspects of CRISPR/Cas for in Vivo Genome Editing

2019

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ConspectusThe discovery of CRISPR/Cas has revolutionized the field of genome editing. CRIPSR/Cas components are part of the bacterial immune system and are able to induce double-strand DNA breaks in the genome, which are resolved by endogenous DNA repair mechanisms. The most relevant of these are the error-prone nonhomologous end joining and homology directed repair pathways. The former can lead to gene knockout by introduction of insertions and deletions at the cut site, while the latter can be used for gene correction based on a provided repair template. In this Account, we focus on the delivery aspects of CRISPR/Cas for therapeutic applications in vivo. Safe and effective delivery of the CRISPR/Cas components into the nucleus of affected cells is essential for therapeutic gene editing. These components can be delivered in several formats, such as pDNA, viral vectors, or ribonuclear complexes. In the ideal case, the delivery system should address the current limitations of CRISPR gene editing, which are (1) lack of targeting specific tissues or cells, (2) the inability to enter cells, (3) activation of the immune system, and (4) off-target events.To circumvent most of these problems, initial therapeutic applications of CRISPR/Cas were performed on cells ex vivo via classical methods (e.g., microinjection or electroporation) and novel methods (e.g., TRIAMF and iTOP). Ideal candidates for such methods are, for example, hematopoietic cells, but not all tissue types are suited for ex vivo manipulation. For direct in vivo application, however, delivery systems are needed that can target the CRISPR/Cas components to specific tissues or cells in the human body, without causing immune activation or causing high frequencies of off-target effects.Viral systems have been used as a first resort to transduce cells in vivo. These systems suffer from problems related to packaging constraints, immunogenicity, and longevity of Cas expression, which favors off-target events. Viral vectors are as such not the best choice for direct in vivo delivery of CRISPR/Cas. Synthetic vectors can deliver nucleic acids as well, without the innate disadvantages of viral vectors. They can be classed into lipid, polymeric, and inorganic particles, all of which have been reported in the literature. The advantage of synthetic systems is that they can deliver the CRISPR/Cas system also as a preformed ribonucleoprotein complex. The transient nature of this approach favors low frequencies of off-target events and minimizes the window of immune activation. Moreover, from a pharmaceutical perspective, synthetic delivery systems are much easier to scale up for clinical use compared to viral vectors and can be chemically functionalized with ligands to obtain target cell specificity. The first preclinical results with lipid nanoparticles delivering CRISPR/Cas either as mRNA or ribonucleoproteins are very promising. The goal is translating these CRISPR/Cas therapeutics to a clinical setting as well. Taken together, these current trends seem to favor the use...

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“…Conflicting results have been reported for RAVV infections of NHPs. Although RAVV infection of rhesus macaques was 100% lethal in two studies 83, 145 , complete survival was noted in a separate study 140 . Overall, these studies highlight the need for further comparative analysis of different marburgvirus variants in different animal models.…”

Section: Advances In Animal Modeling Of Marburgvirus Infectionsmentioning

confidence: 97%

Recent advances in marburgvirus research

2019

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Marburgviruses are closely related to ebolaviruses and cause a devastating disease in humans. In 2012, we published a comprehensive review of the first 45 years of research on marburgviruses and the disease they cause, ranging from molecular biology to ecology. Spurred in part by the deadly Ebola virus outbreak in West Africa in 2013–2016, research on all filoviruses has intensified. Not meant as an introduction to marburgviruses, this article instead provides a synopsis of recent progress in marburgvirus research with a particular focus on molecular biology, advances in animal modeling, and the use of Egyptian fruit bats in infection experiments.

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siRNA rescues nonhuman primates from advanced Marburg and Ravn virus disease

Cited by 27 publications

References 30 publications

Distinct Biological Phenotypes of Marburg and Ravn Virus Infection in Macaques

Distinct Biological Phenotypes of Marburg and Ravn Virus Infection in Macaques

Delivery Aspects of CRISPR/Cas for in Vivo Genome Editing

Recent advances in marburgvirus research

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