Inflammation & Allergy-Drug Targets (v.12, #2)

Inhalation Delivery of Protein Therapeutics by Colleen Kane, Karyn O’Neil, Michelle Conk, Kristen Picha (81-87).
Inhaled therapeutics are used routinely to treat a variety of pulmonary diseases including asthma, COPD andcystic fibrosis. In addition, biological therapies represent the fastest growing segment of approved pharmaceuticals.However, despite the increased availability of biological therapies, nearly all inhaled therapeutics are small moleculedrugs with only a single inhaled protein therapeutic approved. There remains a significant unmet need for therapeutics inpulmonary diseases, and biological therapies with potential to alter disease progression represent a significant opportunityto treat these challenging diseases. This review provides a background into efforts to develop inhaled biological therapiesand highlights some of the associated challenges. In addition, we speculate on the ideal properties of a biologic therapy forinhaled delivery.

Reflections on MicroRNAs in Chronic Pulmonary Disease: Looking into the miR-ror and Crystal Ball by James Karras, Guizhen Sun, Jia Tay, Aimee Jackson (88-98).
Chronic respiratory diseases are a significant health problem requiring novel approaches to both complementexisting therapies and provide breakthrough medicines. Recent clinical advances in understanding the behavior of inhaledoligonucleotides provide the impetus for application of this technology to microRNA therapeutics. MicroRNAs areevolutionarily conserved small regulatory RNA molecules involved in tuning gene networks controlling biological andpathological processes. Deletion or overexpression of microRNAs results in phenotypic changes in animal models ofdisease such as cancer, fibrosis, diabetes, and inflammation. Inhibition of microRNAs in preclinical models of asthma,cystic fibrosis, and idiopathic pulmonary fibrosis has shown therapeutic promise. In animals, inhibitors of microRNAsdirectly delivered to the airway at doses suitable for nebulizers or hand-held inhalers up-regulate expression of cohorts ofgenes containing complementary “seed” sequences for specific and directed microRNA binding within their mRNAuntranslated regions. These observations suggest the opportunity to exploit intervention in microRNA biology to createnew therapies for chronic pulmonary disorders.

Engineering Approaches to Develop the Next Generation of Antibodies to Respiratory Targets by Katherine Vousden, Deborah Clarke, David Lowe (99-108).
Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) represent asignificant health burden worldwide and are a major unmet medical need. Asthma affects over 300 million people andleads to 250,000 deaths per year, with an increasing prevalence particularly in developing countries. Although a largeproportion of asthmatics are maintained on beta agonists and corticosteroids, there still remains a group of patients wherethese medicines fail to modulate symptoms and who may therefore benefit from monoclonal antibody based drugs that areaimed at controlling the disease. COPD is a cigarette smoke-driven chronic inflammatory airway disease with anincreasing global prevalence. Given that current therapies fail to prevent disease progression or mortality, this patientpopulation is also a focus for the development of monoclonal antibody therapies.</P><P>At present anti-IgE (omalizumab, Xolair&#174;) is the only monoclonal antibody based drug approved in the respiratory spacefor the treatment of asthma. However, an increasing number of antibodies targeting key mediators/pathways of disease arein clinical development for both asthma and COPD, including targeting the Th2 pathway for asthma (anti-IL-4/5/13) andthe pro-inflammatory cytokine IL-1 for COPD. This review will examine the antibody engineering approaches used todevelop the next generation of antibodies, with a focus on respiratory disease.

Recombinant Protein Based Therapeutics for IPF by Joseph Parker, Michael Kramer, Lynne Murray (109-123).
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and usually fatal interstitial lungdisease of unknown cause [1, 2]. The aetiology of IPF is unknown, although identified risk factors for IPF includecigarette smoking, environmental exposures, microbial agents, age, male gender and gastroesophageal reflux disease(GERD). Genetic factors may also play a role in the aetiology of IPF as familial cases of IPF are described inapproximately 5&#37; of patients with IPF [2]. Nothing has shown significant anti-fibrotic activity in IPF patients and due tothis high unmet medical need, numerous therapeutics are currently under clinical investigation. In this review, we shallfocus on recombinant protein based approaches for the treatment of IPF, with a particular focus on pathophysiology oflung fibrosis using the bleomycin mouse model.

Predicting Drug Efficacy Using Integrative Models for Chronic Respiratory Diseases by Christopher Stevenson, Sriram Sridhar, Jonathan Phillips (124-131).
Animal models are vital instruments of the drug discovery process. In addition to assessing the efficacy ofcandidate molecules, in vivo disease models also help validate the therapeutic potential of molecular targets. Over recentyears, several molecules that have shown efficacy in preclinical models of respiratory diseases have failed to translate intonew medicines for chronic respiratory conditions such as asthma, chronic obstructive pulmonary disease, and idiopathicpulmonary fibrosis. As such, many scientists have argued that these systems are of limited value; however, we proposethat a more careful and thorough approach to the characterization of these models and the interpretation of data generatedusing these systems would improve their translational utility. Herein, we describe two key elements of our strategy aimingto improve the predictive nature of these models: 1) Novel bioinformatics methods that can be used to identify animalmodels that best represent specific patient populations; and 2) Innovative physiological techniques that will improve ourability to discover drugs that can restore the functional capacity of lungs damaged during the course of the disease.

Intravenous Immunoglobul?n Therapy in Dermatology: An Update by Seray Cakmak, At l Cakmak, Muzeyyen Gonul, Arzu K l c, Ulker Gul (132-146).
Intravenous immunoglobulin (IVIG) is a fractioned blood product consisting of IgG antibodies which was firstused in antibody deficiency disorders. It is increasingly being used for several inflammatory and autoimmune conditions.IVIG can also be used in a wide range of dermatological diseases which are difficult to treat including autoimmunebullous skin diseases and toxic epidermal necrolysis. The use of IVIG in dermatological disorders is discussed in thisarticle.

Basophil Activation Test with Indomethacin to Assess Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs: A Preliminary Study by Zamir Calamita, Roseli Silveira Antunes, Andrea Calamita, Wilson Junior, Debora de Cavaretto, Josianne Fukazawa, Odilon Almeida Filho (147-151).
Background: The basophil activation test has been investigated for diagnosing hypersensitivity to non-steroidalanti-inflammatory drugs (NSAIDs). This has not yet been done in relation to indomethacin.</P><P>Objective: First seek to establish the viable concentrations of indomethacin and the diluent propylene glycol (PPG) inrelation to basophils then test this in patients with hypersensitivity to NSAIDs.</P><P>Materials & Methods: The ideal concentrations of PPG and indomethacin were assessed by incubating them withbasophils from an atopic donor and evaluating the intensity of expression of CD63 molecules by means of flowcytometry. We also evaluated the cell viability directly using the trypan blue in seven controls. Then indomethacin wastested in ten patients with hypersensitivity to NSAIDs compared with eight persons in control group.</P><P>Results: In relation to the toxicity of propylene glycol, concentrations less than or equal to 0.5&#37; are safe. There was nocytotoxicity or nonspecific stimulation from using indomethacin at concentrations of 10 mcg/mL, 1 mcg/mL and 0.1mcg/mL. Then indomethacin was tested at concentration of 10 mcg/mL diluted in 0.5&#37; propylene glycol in both groups.There was no statistical difference in the intensity of activation of basophils comparing the group of patients withhypersensitivity to NSAIDs and the control group.</P><P>Conclusions: As a diluent for indomethacin, PPG should be used at concentrations less than or equal to 0.5&#37;. Theindomethacin at concentration of 10 mcg/mL was not able to differentiate patients with and without hypersensitivity toNSAIDs.