Aerosolized Medications for Gene and Peptide Therapy

Abstract

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). 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. 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. 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.

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

“…In this way, the lung epithelial cells are directly accessible (see Figure 1(a)) and the possibility of the gene therapy vector targeting other tissues and organs is reduced. Aerosolization is possible for a range of gene therapy delivery vectors with varying degrees of success [5], although this does require formulation development to protect vectors that are vulnerable to shear forces generated by nebulizers. Promising results have been achieved with the more gentle, vibrating mesh nebulizers, albeit to-date with protein replacement therapy rather than with a gene therapy vector [6].…”

“…This is particularly relevant for in-vivo approaches, where very large quantities of vector may be needed to target whole organs. One problem is that much of the delivered gene therapy agent may be wasted due to inefficient delivery devices, a particular problem for aerosol delivery to the lung and the body’s ability to clear foreign particulate agents [5], an effect that is used to our advantage for liver gene transfer [90]. Crucially, the development of vectors that are more efficient, such that a lower dose is required for efficacy, should also be pursued.…”

Dry powder inhalation: past, present and future

“…It was anticipated that 'in the near future, optimal formulations will be combined with modified aerosol delivery devices to achieve reproducible dosing'. Again 20 years later, it has to be acknowledged that still more efficient aerosol devices are needed, that formulations have to be safer and bioavailability has to be improved [169]. McElroy et al compared the results for inhaled proteins from different studies, showing that systemic bioavailability for compounds with mol weights (MWs) <10 kDa can vary from almost 0% to 100%, whereas for MWs >10 kDa, 60% is maximal (so far) [170].…”

Recent Advances and Future Prospects of Non-Invasive Insulin Delivery Systems

“…Exubera ® was the first officially approved pulmonary insulin product by the FDA in 2006 [48,49]. The human insulin powder in blisters was taken using Exubera ® inhaler ( fig.…”