**11. Conclusion**

mutation in which the protein traffics the cell surface but the channel does not function properly. Kalydeco interacts with the channel and increases the open probability of the channel. Another Vertex product, currently titled VX-809, is designed to act in patients with class II mutations (i.e., ΔF508). VX-809 acts in the endoplasmic reticulum, allowing improp‐ erly folded CF protein to pool and undergo corrected folding which results in trafficking to the cell membrane. [93] Both Vertex products are the result of so-called high throughput small molecule screening in which hundreds of thousands of small molecules are screened in a recombinant cell-based assay for an effect on cell function. The discovery of drugs that address the underlying genetics cause is an exciting advancement in any genetic disease, but made even more so by the fact that CF is one of the more common, and fatal diseases caused by a genetic malformation. Whether any of these drugs change the number or activation

Patients with COPD, an even larger cohort than those with CF may also soon benefit from new therapies targeted at resolving the underlying cause rather than merely treating symp‐ toms. There is currently only a single phosphodiesterase 4 (PDE4) inhibitor, Daliresp that is approved for treatment of COPD in the United States. However, there are clinical trials cur‐ rently underway researching the effects of multiple other PDE4 inhibitors. [94] PD4 is a cAMP specific phosphodiesterase present, primarily, in inflammatory cells and also in epi‐ thelial cells. Treatment with Daliresp has been shown to reduce the release of pro-inflamma‐ tory cytokines by neutrophils and resident monocyte/macrophages. Unfortunately, there are several side effects associated with Daliresp and thus the need for better, more targeted PDE4 inhibitors is apparent. Additionally, there have been recent advancements made in traditional COPD therapies. The development of ultra-long acting β2 agonists has proved beneficial in a number of lung diseases, including COPD, A1AT, and asthma. [95] Research is also underway into the identification of biomarkers for smokers who will develop COPD, allowing treatment or prevention to possibly begin earlier. Investigators at Weill Cornell College of Medicine are using a metabolomics approach in a cohort of smokers to establish a thorough catalogue of abnormal cell changes in airway epithelium after cigarette smoking. (weill.cornell.edu) Utilizing serum, epithelial lining fluid, and airway epithelial samples, Dr. Crystal's group aims to identify the early changes in airway epithelium that indicate if a pa‐

McNab et al recently published work detailing their investigation of "compound cg," a small molecule that assists in reducing aggregates of abnormal A1AT protein. [96] GC was effective in an *in vitro* model of A1AT deficiency and showed significant reduction in At1AT aggregates by both immunohistochemistry and Western blot analysis. Gene therapy is an‐ other approach, also applicable to CF that is being investigated as a potential source of cur‐ ing the disease in A1AT deficiency. A group at UMass has pioneered a dual gene therapy approach that addressed both the lung malfunction and liver disease so often associated with aggregation of mutant protein. In utilizing an adeno-associated virus (AAV) to intro‐ duce corrected protein product in the lung, and microRNAs (miRNA) in the liver to reduce production of dysfunctional protein, the investigators have presented the possibility of cura‐

state of PMNs in the airway is currently unknown

114 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

tient will develop COPD later.

tive therapy for patients with A1AT deficiency. [97]

Chronic neutrophilic airway inflammation is a clinically similar, but foundationally hetero‐ geneous cohort of disease. Although neutrophils are necessary and effective components of the innate immune system in resolving infection, when dysregulated, they can be potent me‐ diators of devastating inflammation. Current therapeutics in a variety of neutrophilic lung diseases fail to address the underlying causes of the conditions and yield questionable bene‐ fit to patients. Fortunately, advances in identifications of biomarkers such as PGP and others afford the opportunity to develop targeted therapeutics aimed at resolving and preventing the progressive destruction that is a hallmark of chronic neutrophilic lung disease.
