Molecular Therapy, Vol 25 S1, Abstract 199
The American Society of Gene and Cell Therapy Annual Conference, Washington, DC, 2017
Respiratory syncytial virus (RSV) infection is the single most common cause of hospitalisations in infants under 1 year of age. Globally, the virus is responsible for an estimated 33.8 million incidents of acute lower respiratory infections in children younger than 5 years (Lancet 375:1545, 2010).
In the US alone, approximately 2.1 million children under 5 years of age require medical attention every year due to RSV infection, of which 3% need hospitalisation (N Engl J Med 360:588, 2009). There is currently no vaccine against RSV. Prophylaxis with monoclonal antibody palivizumab (Synagis, MedImmune) is effective, and reduces hospitalisation rates by 55% in infants up to 6 months of age (Pediatrics 102:531, 1998). Next generation antibodies are being developed, with improved efficacy and half-life. The use of antibodies for RSV prophylaxis is however costly due to the complexity of large-scale manufacture, and thus only offered to select vulnerable infant populations, such as children with chronic lung disease, congenital heart disease, or preterm infants. Therefore we are developing gene delivery approaches to establish 'protein factories' for direct expression of palivizumab and other antibodies in patients. Recombinant adeno-associated virus (rAAV2/8) was used for delivery to the gastrocnemius muscle of BALB/c mice, with transgene expression under the control of the CASI promoter (Nature 481:81, 2011).
Recombinant Simian Immunodeficiency Virus (SIV) pseudotyped with Sendai virus envelope proteins F and HN (Thorax 72:137, 2017) (rSIV.F/HN), with transgene expression from the hCEF promoter (Nat Biotech 26:549, 2008) was delivered to the mouse lung via insufflation. We performed proof of concept studies in mice using vectors expressing secreted Gaussia luciferase (GLux) reporter protein. Delivery of either vector (1E6, 1E7 or 1E8 TTU of rSIV.F/HN delivered intranasally in 100 µl; 1E9, 1E10 or 1E11 GC of rAAV2/8 delivered IM in 40 µl) resulted in sustained reporter expression in the lung lumen, measured in broncho-alveolar lavage fluid (BALF) (p800-fold greater GLux expression in the circulation compared with the lentiviral vector, but intranasal delivery of rSIV.F/HN yielded >900-fold greater reporter levels in the BALF compared with AAV. Next, recombinant SIV and AAV vectors were constructed expressing palivizumab. Following delivery to mice, therapeutically relevant serum levels of the antibody were achieved using rAAV for at least 6 months (89.3 µg/ml at 6 months post-delivery of 1E11 GC/mouse; p<0.001).
Furthermore, both delivery vectors resulted in palivizumab secretion into the lung at 1 month (p
We speculate that, if successful, this approach could significantly reduce per dose treatment costs, which could allow for wider use of prophylaxis against RSV infection in the continued absence of an effective vaccine.