**3. PXS TPI1100: The drug**

438 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

are reasons PDEs are good drug targets as selective inhibition of a specific PDE isoform

Another reason PDEs have been the focus of drug companies is based on the pharmacologic principle that a more rapid and larger percentage change in concentration is achieved through regulating the degradation of a second messenger than comparable regulation of the rates of synthesis (Bender &Beavo 2006). In most cells the levels of cAMP are between <1 to 10 µM which enables a competitive inhibitor to not need to compete with high levels of endogenous substrate to be effective, in contrast to many protein kinase inhibitors which need to have sufficient affinity to displace mM concentrations of ATP (Bender &Beavo

There are four PDE4 (A/B/C/D) genes which generate multiple variants as a result of splicing differences in their N termini (Bender &Beavo 2006). PDE4 isoforms, which are widely expressed in many tissues and cell types including the lung, have been shown to play a key role in macrophage and monocyte activation and functions, neutrophils infiltration and vasodilation (Table 1). There has been more information collated on PDE4 than other PDEs mostly from the work resulting from PDE4A, 4B and 4D knock out mice. In PDE4D knockout mice, their airways were shown to be refractory to cholinergic stimulation (Mehats et al. 2003) while PDE4B knockout mice were shown to have effects on immune cells (Jin &Conti 2002; Jin et al. 2005) and both genes were shown to be required for neutrophils recruitment in a model of lung injury in response to inhaled endotoxin (Ariga et

A new first-in class treatment, the PDE4 inhibitor Daxas/Daliresp (Nycomed), has recently been approved in Europe in 2010 and in the USA in 2011 for patients with severe COPD.

Table 1. Expression of different cAMP-modulating PDE isoforms in lung cells and

and PDE7 in both lung structural and inflammatory cells.

inflammatory cells. PDE4 and PDE7 are highly expressed in lung structural cells as well as in inflammatory cells. Delivered to the lung, PXS TPI1100 can inhibit expression of PDE4

would limit nonspecific sides effects associated with broader PDE inhibition.

2006).

al. 2004).

The relative lack of advancement and the slow pace of innovation to identify new drug products for COPD can be indicative of the complicated nature of this chronic diseases as well as a potential limited number of targets for conventional small molecule drugs and biologics. Moreover, the activity of cytokines, growth factors and chemokines depends on the interaction of these proteins with their cell surface receptors involving large proteinprotein interactions or involving interactions between multiple sites on the protein, which could be particularly challenging to disrupt with small molecule inhibitors or biologics (Johnson et al. 2005). To side-step these complications, we have attempted to design an antisense oligonucleotide (AON) based therapy which functions by targeting RNA directly rather than the protein product.
