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One early pioneer in the respiratory field was the AON drug EPI 2010 (Epigenesis) targeting the promoter region of the adenosine A1 receptor. Although demonstrating efficacy *in vitro* and in animal models (Ball et al. 2004), EPI 2010 failed in later clinical studies to demonstrate efficacy to improve lung function in asthmatics. With the more recent understanding of the role the different adenosine receptors have in asthma (Brown et al. 2008), it could be argued that the absence of clinical efficacy for EPI 2010 could either be a result of targeting the wrong adenosine receptor or perhaps the need to combine it with other adenosine receptor inhibitors. Similarly, early preclinical efficacy and effect on biomarkers in a phase 1 study with AIR-645 (AON targeting IL-4/IL-13Rα Altair/Isis) met with apparent insufficient efficacy on lung function in phase 2 study (personal communication). This may perhaps be attributed to the target selection as other non-ODN drugs targeting these receptors have also had limited success in clinical trials. As mentioned, although few PDE7 inhibitors have been tested in clinical studies, our preclinical pharmacology results indicate a clear benefit in targeting this PDE isoform along with the PDE4. There is growing acceptance that multitargeted approaches may provide significant therapeutic advantages, as demonstrated by the issuance of new guidance on drug combinations by the Food and Drug Administration. There is a clear need for innovative products with novel mechanisms of action to complement today's inhaled products particularly for severe patients who seem resistant to current therapeutic interventions. In spite of many attempts, success in these respiratory indications has been modest, at most. This may reflect the challenge of delivering the therapies to the site of action (lung) or more importantly the complexity of these diseases. PXS TPI1100 belongs to a new class of therapeutics that is poised to expand in the upcoming decades because of its advantages, especially with lung administration. Outstanding challenges for PXS TPI1100 remain the need to establish long term safety and tolerability data as well as commence clinical

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**23** 

*Brazil* 

**Cell Therapy in Chronic** 

**Obstructive Pulmonary Disease:** 

**State of the Art and Perspectives** 

*University of the State of São Paulo – UNESP, Campus Assis* 

João Tadeu Ribeiro-Paes, Talita Stessuk and Rodrigo de las Heras Kozma *Laboratory of Genetics and Cell Therapy, GenTe Cel, Department of Biological Sciences,* 

The pulmonary diseases of obstructive character have high prevalence in the human population and has been subject of several clinical and experimental studies in order to seek a wider understanding of their pathogeny, physiopathology and, especially, the establishment of more rational ways for their treatment. Accordingly, this great effort has led to an extraordinary widening in the concepts of obstructive diseases in the last years, involving the integration of mechanical factors, inflammatory agents, autonomic regulation

The COPD may be understood as a pathologic condition in which a non-reversible and limited gas exchange occurs. There are two clinical entities that constitute the COPD: chronic bronchitis and emphysema. Within the COPD spectrum, the main characteristic of pulmonary emphysema is air flow blockage and progressive dyspnea, arising out of the impairment of alveolar walls and increase of air spaces distal to terminal bronchiole, without significant pulmonary fibrosis (Barnes et al., 2003; GOLD, 2009; Oliveira et al.,

The oxidative damage to which lungs are submitted to, as well as the inflammation occurring as a response to irritant agents, such as those coming from air pollution and cigarette smoke, contributes to the induction of the pulmonary degeneration (Lee et al., 2011). Therefore, it may be concluded that chief characteristic of COPD is the acceleration of functional and morphologic loss, with limitation of gas exchanges, resulting in progressive

Therefore, the development and progression of the pathology are resulting from the interaction of genetic and environmental factors (Ribeiro-Paes et al., 2009). About 1-3% of cases of emphysema are generated by enzyme α1-antitrypsin deficiency, that characterizes a genetic abnormality as an inheritance of autossomal recessive pattern. The other risk factors include: age, infections, as well as social and economic factors (Mannino & Buist, 2007).

Smoking, however, has been established as the major cause related with COPD, resulting for active or passive exposure to the cigarette smoke, and corresponds to 15-20% of cases of

**1. Introduction**

2000).

of airways and environmental aspects.

dyspnea, disability and premature death.

