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 321

vaccines, and fusion protein inhibitors, no approach has generated positive clinical
data leading to FDA approval of a new RSV therapeutic [ 7 ]. A positive result in the
ALN-RSV01-109 trial has the potential to lead to the development of a novel thera-
peutic for lung transplant patients who are at risk of developing BOS and chronic
graft dysfunction after RSV infection. In addition, if ALN-RSV01 is found to be
clinically efficacious in lung transplant patients, it opens up the possibility that it may
also be beneficial in other high-risk populations that do poorly when infected with
RSV, such as bone marrow transplant patients, the elderly, and pediatric patients with
prematurity or congenital heart disease. Targets like RSV that are exogenous to the
lung as well as those that are endogenous to the lung (e.g., airway epithelial genes)
are potentially amenable to modulation by an RNAi therapeutic delivered via nebuli-
zation, thereby limiting systemic exposure, and thus will likely continue to be a focus
of research in the RNAi field and in pulmonary medicine over the next decade.
Over the past 20 years, RNAi has gone from being a Nobel Prize-worthy scientific
discovery in plants and worms to a novel therapeutic approach that can be utilized
to silence the expression of genes that play a role in human disease. To date, ~15
clinical programs have administered siRNA both locally (e.g., to the eye or lung)
and systemically (e.g., intravenously), and these approaches have been shown to be
safe and well-tolerated in both healthy human volunteers as well as patients [ 40,
41 ]. In particular, formulation of siRNAs in lipid nanoparticles has led to significant
breakthroughs in systemic delivery. Recently, two separate Phase I clinical trials
have reported that LNP-formulated siRNA can safely and effectively inhibit the
expression of two liver-derived genes, PCSK9 and TTR, in healthy volunteers and
patients, respectively [ 42, 43 ]. While RNAi is still in the early phases of clinical
investigation, the emerging safety and efficacy data suggest that RNAi will translate
into meaningful therapeutics for human disease.
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