Preclinical and Clinical Studies Employing RNA Interference as a Therapeutic for Respiratory Syncytial Virus (RSV) Infection in the Lung - RNA Interference from Biology to Therapeutics - page 312

mechanical ventilation is dependent on the subject's age and underlying health
status: for example, it is required in 14% of hospitalized infants versus in 30% of
children who have chronic lung disease [ 8 ]. Strict infection control measures are
also employed to prevent hospital outbreaks. Pharmacotherapy may include bron-
chodilators and corticosteroids, depending on the age and severity of the infection.
Ribavirin, a nucleoside analogue with in vitro activity against RSV, is currently the
only drug that is approved for use in RSV infection by the US Food and Drug
Administration (FDA) and is typically administered by inhalation, although IV and
oral administration are also used. The routine use of ribavirin, however, is not rec-
ommended by the American Academy of Pediatrics and is reserved for immunosup-
pressed patients with severe infection [ 9 ]. In mainly retrospective studies, the use of
ribavirin in bone marrow patients infected with RSV resulted in a lower rate of pro-
gression of disease to the LRT as well as decreased mortality [ 10 ] . Ribavirin is also
administered to patients with solid organ transplants with RSV infection; however,
the efficacy of this is less clear [ 11 ] .
Standard immunoglobulins (IVIG) and RSV-specific immunoglobulins (RSV-
IVIG) have also been used for prophylaxis and treatment in high-risk children.
RSV-IVIG was approved by the FDA in 1996 for prophylaxis in high-risk children,
but is no longer available. Palivizumab (PVZ), a humanized monoclonal antibody
against the RSV fusion protein, has also been in use since 1998 for RSV infection
prophylaxis in high-risk children, including premature infants, and children with
bronchopulmonary dysplasia or congenital heart disease [ 12 ] . While still controver-
sial, immune modulators (e.g., PVZ and IVIG) are also used alone or in combina-
tion with ribavirin to treat adults with severe RSV infection. Combining ribavirin
with immune modulators has also shown a trend toward improved outcome with
regard to progression to LRTI or death, in adult hematopoietic stem cell transplant
patients over ribavirin alone [ 10 ]. Given the unclear efficacy of ribavirin, along with
its significant side effect profile (e.g., teratogenicity of the inhaled product) and
ability to induce viral resistance, safer and more effective agents are needed for both
RSV treatment and prophylaxis in pediatric as well as adult populations [ 13, 14 ] .

15.1.3 Scienti fi c Rationale for Targeting

the RSV Nucleocapsid Gene

RSV has a negative single-strand RNA genome-encoding nonstructural proteins
(NS2, NS1) and several other proteins such as nucleocapsid (N), phosphoprotein
(P), and RNA-dependent RNA polymerase (L). The N, P, and L proteins are con-
tained within the nucleocapsid of the virion and are required for steps in the RSV
replication cycle. Consistent with their absence from the outer virus surface, and
their crucial role in viral replication, the RNAs encoding the N, P, and L proteins are
among the most highly conserved regions of the RSV genome [ 15 ] . Therefore,
siRNAs targeting these mRNAs would be expected to result in potent inhibition of
viral replication across a wide range of RSV strains. Recent studies have demonstrated