Biomedical Engineering Reference
In-Depth Information
5
′
UTR of GBV-B repressed GBV-B replication in a dose-dependent
manner. However, since elevated levels of serum IFNs were observed
upon siRNA treatment, the study concluded that the observed
antiviral eff ect was attributable to both RNAi as well as activation
of innate immune responses. Nevertheless, the promising results
with siRNAs, shRNAs and lhRNAs targeting structural (i.e., core and
envelope) and nonstructural proteins, the HCV IRES and CD81, the
human receptor for HCV in cell culture assays (reviewed in [56, 64])
indicate that RNAi based approaches is a feasible therapy for HCV
infection.
7.3.4
SARS Coronavirus (SARS-CoV)
The SARS epidemic, which started in November 2002 in the People's
Republic of China spread to 29 countries, resulted in more than
8,000 cases and 744 reported deaths within a year [114]. By July
2003, a novel coronavirus, SARS-CoV was identified as the etiological
agent of SARS [69]. SARS-CoV, like other coronaviruses, has a
large positive-sense RNA genome encoding 14 ORFs, including 2
overlapping reading frames ORF 1a and 1b, which account for more
than two-thirds of the genome [131]. While vaccine and therapeutic
drug development have been an area of ongoing research since the
outbreak, neither are currently approved for use [107]. This has
highlighted the need for novel treatments like RNAi-based ones.
Two siRNAs targeting the mRNA encoding the spike protein and
non-structural protein 12 were identified in a screen for potent
conserved RNAi targets conducted in SARS-CoV-infected Rhesus
monkey kidney (FRhK-4) cells [131]. These were further validated
for the prophylactic and therapeutic treatment of SARS infection
in a Rhesus macaque model [77]. Reporter gene assays in mice
demonstrated that both siRNAs, administered intratracheally in
D5W (5% dextrose/water solution) were eff ectively delivered to the
lungs and were able to eff ectively reduce luciferase expression from
reporters bearing the target sequences. Furthermore, SARS-CoV
infected macaques treated intranasally (i.n.) with the two siRNAs
individually or in combination showed significantly lower body
temperatures when treated prior to or after being infected, although
siRNA dosages varied from 30 to 120 mg over a 120h treatment time.
The best prognosis was seen in macaques on a prophylactic regimen
with the smallest dose of 30mg siRNA. The treatment provided
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