Lin G et al. (2005) Improving erectile function by silencing phosphodiesterase-5. J Urol 174: 1142–1148

Despite the popularity of sildenafil and other phosphodiesterase-5 (PDE5) inhibitors for the treatment of erectile dysfunction, these drugs show little benefit in about a third of patients. In addition, some patients experience adverse effects such as headache and facial flushing. In an attempt to find a superior treatment, Lin and colleagues have explored the idea of using small interfering RNA (siRNA) to suppress PDE5 expression at the mRNA level.

The researchers selected a 19-base region of human PDE5 cDNA thought to be identical in the rat. They incorporated this sequence into a double-stranded, 64-base oligonucleotide and cloned this into a vector to produce the 'pPDE5-silencer' construct. They then demonstrated that rat and human cavernous smooth-muscle cells transfected with this construct produced lower levels of PDE5 than those transfected with 'empty' vector. This was accompanied by prolonged cGMP accumulation in the treated cells.

Next, they transferred the siRNA-expressing cassette to a lentiviral vector and injected this into the penises of nine Sprague-Dawley rats. Cavernous nerve electrostimulation tests 3 months later showed that the siRNA-treated rats had enhanced erectile function compared with nine rats treated with vector alone. This finding was reinforced by immunohistochemical staining experiments, which showed lower PDE5 levels in the cavernous smooth muscle of the treated animals.

In summary, these studies demonstrate that a PDE5 siRNA method can decrease PDE5 expression and improve erectile function in rats. A new therapy for erectile dysfunction based on this technique appears promising.