Role for animal models in understanding essential fatty acid deficiency in cystic fibrosis.

Essential fatty acid deficiency has been observed in most patients with Cystic Fibrosis (CF); however, pancreatic supplementation does not restore the deficiency, suggesting a different pathology independent of the pancreas. At this time, the underlying pathological mechanisms are largely unknown. Essential fatty acids are obtained from the diet and processed by organs including the liver and intestine, two organs significantly impacted by mutations in the cystic fibrosis transmembrane conductance regulator gene (Cftr). There are several CF animal models in a variety of species that have been developed to investigate molecular mechanisms associated with the CF phenotype. Specifically, global and systemic mutations in Cftr which mimic genotypic changes identified in CF patients have been generated in mice, rats, sheep, pigs and ferrets. These mutations produce CFTR proteins with a gating defect, trafficking defect, or an absent or inactive CFTR channel. Essential fatty acids are critical to CFTR function, with a bidirectional relationship between CFTR and essential fatty acids proposed. Currently, there are limited analyses on the essential fatty acid status in most of these animal models. Of interest, in the mouse model, essential fatty acid status is dependent on the genotype and resultant phenotype of the mouse. Future investigations should identify an optimal animal model that has most of the phenotypic changes associated with CF including the essential fatty acid deficiencies, which can be used in the development of therapeutics.

Public Acceptability of Gene Therapy and Gene Editing for Human Use: A Systematic Review.

Gene therapy and gene editing technologies are complex and it can be difficult for the public to understand their possible benefits or side effects. However, patient and public support is critical for the successful adoption of any new technology. Given the recent advances in gene therapy and gene editing, their potential clinical benefits, and the significant attention that has been given to the first-known successful attempt at permanent and heritable changes to the human genome, a systematic review was performed to assess beliefs and attitudes toward gene therapy and gene editing for human use, and to highlight the factors that influence acceptability. A systematic search following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was undertaken in April 2018 to identify articles examining opinions and attitudes regarding the acceptability of gene therapy and gene editing. Overall, 1,561 records were retrieved from 4 databases (Ovid Medline, PsycINFO, Scopus, and Web of Science). Duplicates were removed, and titles and abstracts independently screened, leaving 86 full-text articles assessed for eligibility. Following full-text review, 33 were included, with 5 articles added after forward/backward searching. An additional three articles were added following an updated search in March 2019 (total n = 41). Findings from the studies were integrated according to common themes: the impact of demographics; risks versus benefits of success; treatment specifics (e.g., medical vs. other reasons; disease severity and status; somatic vs. germ line; and mode of delivery); moral or ethical issues; and changes with time. In general, perceptions were positive, particularly for medical reasons and fatal diseases, but were also influenced by perceived risk. Somatic therapies had higher levels of acceptability than germ line therapies. While available in various forms, limitations exist in the measurement of perceptions of gene therapy and gene editing. Treatment acceptability is essential for future clinical trials, so it is important for scientists and clinicians to be clear about the risks and benefits of these technologies, and how these are communicated to the public, while encouraging education about genetic therapies to a broad range of individuals.

Multimodal Precision Imaging of Pulmonary Nanoparticle Delivery in Mice: Dynamics of Application, Spatial Distribution, and Dosimetry.

Targeted delivery of nanomedicine/nanoparticles (NM/NPs) to the site of disease (e.g., the tumor or lung injury) is of vital importance for improved therapeutic efficacy. Multimodal imaging platforms provide powerful tools for monitoring delivery and tissue distribution of drugs and NM/NPs. This study introduces a preclinical imaging platform combining X-ray (two modes) and fluorescence imaging (three modes) techniques for time-resolved in vivo and spatially resolved ex vivo visualization of mouse lungs during pulmonary NP delivery. Liquid mixtures of iodine (contrast agent for X-ray) and/or (nano)particles (X-ray absorbing and/or fluorescent) are delivered to different regions of the lung via intratracheal instillation, nasal aspiration, and ventilator-assisted aerosol inhalation. It is demonstrated that in vivo propagation-based phase-contrast X-ray imaging elucidates the dynamic process of pulmonary NP delivery, while ex vivo fluorescence imaging (e.g., tissue-cleared light sheet fluorescence microscopy) reveals the quantitative 3D drug/particle distribution throughout the entire lung with cellular resolution. The novel and complementary information from this imaging platform unveils the dynamics and mechanisms of pulmonary NM/NP delivery and deposition for each of the delivery routes, which provides guidance on optimizing pulmonary delivery techniques and novel-designed NM for targeting and efficacy.