![]() In the case of adenoviruses, the deoxyribonucleic acid (DNA) does not integrate into the host genome, and so its effects are transient, lasting only 7–42 d. This is problematic since aerosolized gene therapy will likely require repeat dosing because mucus clearance mechanisms and/or phagocytes may engulf and destroy the drug vector before it can be taken up by all the targeted cells. It is clear from Table 1 that one of the main drawbacks to the use of adenoviral or adeno-associated viral vectors is the high probability of inducing an acute immune response upon initial administration or reduced efficacy following repeat dosing, respectively. Results from clinical and preclinical studies are highlighted, and delivery devices are featured if they appear critical to the success of the application. The status and challenges facing each of these new applications are presented. This paper focuses on newer aerosol therapies for oral inhalation, including: (1) aerosolized gene therapies to treat lung cancer, Mycobacterium tuberculosis, alpha-1 antitrypsin deficiency, and cystic fibrosis (CF) (2) aerosolized peptides to treat asthma, sarcoidosis, pulmonary hypertension, CF, and pulmonary alveolar proteinosis and (3) aerosolized peptides to treat diseases outside the lung whose target is systemic circulation. Traditional aerosol therapies consist of short- and long-acting β 2-adrenergic agonists, anticholinergics, steroidal and non-steroidal anti-inflammatories, antibiotics, and mucolytics. This route of administration provides a more rapid onset of action for short-acting bronchodilators compared with oral therapy, high local drug concentration by delivery directly to the airways, needle-free systemic delivery of drugs with poor oral bioavailability, and pain- and needle-free delivery of drugs that require subcutaneous or intravenous injection. There are many advantages to administering medications to the lung as an aerosol. granulocyte-macrophage colony-stimulating factor (GM-CSF).The success of these new aerosol applications will depend on many factors, such as: (1) developing gene therapy formulations that are safe for acute and chronic administrations to the lung, (2) improving the delivery of the genetic material beyond the airway mucus barrier and cell membrane and transferring the material to the cell cytoplasm or the cell nucleus, (3) developing aerosol devices that efficiently deliver genetic material and peptides to their lung targets over a short period of time, (4) developing devices that increase aerosol delivery to the lungs of infants, (5) optimizing the bioavailability of systemically delivered peptides, and (6) developing peptide formulations for systemic delivery that do not cause persistent cough or changes in lung function. Drugs that are highlighted include: small interfering ribonucleic acid to treat lung cancer and Mycobacterium tuberculosis vectors carrying the normal alpha-1 antitrypsin gene to treat alpha-1 antitrypsin deficiency vectors carrying the normal cystic fibrosis transmembrane conductance regulator gene to treat cystic fibrosis vasoactive intestinal peptide to treat asthma, pulmonary hypertension, and sarcoidosis glutathione to treat cystic fibrosis granulocyte-macrophage colony-stimulating factor to treat pulmonary alveolar proteinosis calcitonin for postmenopausal osteoporosis and insulin to treat diabetes. These newer applications for aerosol therapy are the focus of this paper, and I discuss the status of each and the challenges that remain to their successful development. ![]() Inhalation therapy has matured to include drugs that: (1) deliver nucleic acids that either lead to the restoration of a gene construct or protein coding sequence in a population of cells or suppress or disrupt production of an abnormal gene product (gene therapy) (2) deliver peptides that target lung diseases such as asthma, sarcoidosis, pulmonary hypertension, and cystic fibrosis and (3) deliver peptides to treat diseases outside the lung whose target is the systemic circulation (systemic drug delivery).
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