Respirable antisense oligonucleotide (RASON) therapy for allergic asthma.
A new technology for treating respiratory disease, respirable antisense oligonucleotides (RASONs), has recently been developed by our group. RASONs are short, single-stranded nucleic acids, generally modified to reduce degradation. They differ from traditional drugs, which usually antagonise preformed proteins already functioning in a disease process. Instead, RASONs can attenuate the expression of disease-associated genes by targeting the messenger RNA (mRNA). Delivered directly to the target tissue, the lung, they avoid the problems of ineffective delivery encountered by other routes of administration. When an adenosine A(1) antisense oligonucleotide was delivered to the lungs of allergic rabbits with up-regulated A(1) adenosine receptors, desensitisation to the bronchoconstrictor effects of adenosine, histamine and a common aeroallergen (dust mite) occurred. The effect on A(1) receptors persisted on average for nearly 7 days. RASON (the phosphorothioate antisense oligonucleotide EPI-2010) administered in low dosage was evenly distributed throughout the lung (with no detectable systemic active metabolites), and was excreted primarily in urine. These results demonstrate that RASONs can be efficiently and effectively delivered to the peripheral lung. They potently and selectively attenuate the expression of disease-associated genes, an approach to therapy which is now being extended to other potentially important mediators of bronchial asthma.
Metzger
W J
WJ
Section of Allergy, Asthma & Immunology, East Carolina University School of Medicine, Greenville, NC, USA.
Nyce
J W
JW