Will Airway Gene Therapy for Cystic Fibrosis Improve Lung Function? New Imaging Technologies Can Help Us Find Out

Abstract

The promise of genetic therapies has turned into reality in recent years, with new first-line treatments for fatal diseases now available to patients. The development and testing of genetic therapies for respiratory diseases such as cystic fibrosis (CF) has also progressed. The addition of gene editing to the genetic agent toolbox, and its early success in other organ systems, suggests we will see rapid expansion of gene correction options for CF in the future. Although substantial progress has been made in creating techniques and genetic agents that can be highly effective for CF correction in vitro, physiologically relevant functional in vivo changes have been largely prevented by poor delivery efficiency within the lungs. Somewhat hidden from view, however, is the absence of reliable, accurate, detailed, and noninvasive outcome measures that can detect subtle disease and treatment effects in the lungs of humans or animal models. The ability to measure the fundamental function of the lung-ventilation, the effective transport of air throughout the lung-has been constrained by the available measurement technologies. Without sensitive measurement methods, it is difficult to quantify the effectiveness of genetic therapies for CF. The mainstays of lung health assessment are spirometry, which cannot provide adequate disease localization and is not sensitive enough to detect small early changes in disease; and computed tomography, which provides structural rather than functional information. Magnetic resonance imaging using hyperpolarized gases is increasingly useful for lung ventilation assessment, and it removes the radiation risk that accompanies X-ray methods. A new lung imaging technique, X-ray velocimetry, can now offer highly detailed regional lung ventilation information well suited to the diagnosis, treatment, and monitoring needs of CF lung disease, particularly after the application of genetic therapies. In this review, we discuss the options now available for imaging-based lung function measurement in the generation and use of genetic and other therapies for treating CF lung disease.

Future of genetic therapies for rare genetic diseases: what to expect for the next 15 years?

“…22,53,77 The effectiveness of gene therapy -which uses a vector to deliver a functional gene into the cell -is directly related to the vectors' ability to transfer the gene without activating oncogenes or generating immune or inflammatory reactions. 15,17 Activation of oncogenes has been reported in clinical trials of gene therapies in which patients developed leukemia related to the viral vector used in the treatment, in this case retrovirus. 2,53 For its part, immune and inflammatory reactions may reduce the effectiveness of the treatment and even make new attempts impossible because the patient's immune system may start recognizing and rejecting the vector.…”

“…2,53 For its part, immune and inflammatory reactions may reduce the effectiveness of the treatment and even make new attempts impossible because the patient's immune system may start recognizing and rejecting the vector. 17,32 While viral vectors such as AAV, lentivirus, and retrovirus may cause immune or inflammatory reactions, they are widely used in gene therapy because they are very effective in delivering the functional gene into the cell. 35,46 For example, Luxturna and Zolgensma, the FDA-approved gene therapies for genetic diseases, are both AAVbased.…”

“…8,[13][14][15][16] The ideal genetic therapy should fix defective genes without activating oncogenes or causing off-target effects or immune or inflammatory reactions. [17][18][19] Proto-oncogenes are genes responsible for cell growth and proliferation. When there is a change in the chromosome, they can suffer a mutation and become an oncogene.…”

“…Some studies have already tried to anticipate the potential of genetic therapies for rare genetic diseases. Most are literature review articles reporting on genetic therapy research for a specific rare genetic disease, such as hemophilia, 36 cystic fibrosis, 17 , 37 spinal muscular atrophy, 38 retinitis pigmentosa, 39 achromatopsia, 40 Bardet–Biedl syndrome, 11 and Leigh syndrome. 41 Others have investigated their potential in other areas, such as cancer, 42 – 44 Parkinson’s disease, 45 Alzheimer’s disease, 45 and immunodeficiencies.…”

Anticipating New Treatments for Cystic Fibrosis: A Global Survey of Researchers

“…Then, we generated a list of their Digital Object Identifiers (DOIs) and imported it into the reference management software Citavi 6.1, where these references were downloaded in a PDF format and fully read. After this process, we considered 47 [ 6 , 8 , 9 , 10 , 20 , 22 , 23 , 24 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ] references appropriate to the study and used them in the literature review that allowed us to draft the survey questionnaire.…”