Aerosol Delivery of DNA/Liposomes to the Lung for Cystic Fibrosis Gene Therapy

Davies, Lee A.; Nunez-Alonso, G.; McLachlan, Gerry; Hyde, Stephen C.; Gill, Deborah R.

doi:10.1089/humc.2014.019

Cited by 47 publications

(39 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the latter study, monthly aerosol administration of DNA/liposomes was sufficiently effective to produce significant improvements in lung function. Non-viral vectors are usually based on cationic lipids [16,17] or polymers [18], encapsulating plasmid DNA or siRNA species. Unlike most viral vectors, non-viral vectors lack an active mechanism to import their genome into the nucleus of targeted cells, although passive import features can be added by the incorporation of tissue-specific DNA nuclear import signals found in certain promoter sequences, including the lung-specific SP-C promoter [19].…”

Section: A Brief History Of In-vivo Gene Therapymentioning

confidence: 99%

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

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

Self Cite

View full text Add to dashboard Cite

Introduction: Ex-vivo gene therapy has had significant clinical impact over the last couple of years and in-vivo gene therapy products are being approved for clinical use. Gene therapy and gene editing approaches have huge potential to treat genetic disease and chronic illness. Areas covered: This article provides a review of in-vivo approaches for gene therapy in the lung and liver, exploiting non-viral and viral vectors with varying serotypes and pseudotypes to target-specific cells. Antibody responses inhibiting viral vectors continue to constrain effective repeat administration. Lessons learned from ex-vivo gene therapy and genome editing are also discussed. Expert opinion: The fields of lung and liver in-vivo gene therapy are thriving and a comparison highlights obstacles and opportunities for both. Overcoming immunological issues associated with repeated administration of viral vectors remains a key challenge. The addition of targeted small molecules in combination with viral vectors may offer one solution. A substantial bottleneck to the widespread adoption of in-vivo gene therapy is how to ensure sufficient capacity for clinical-grade vector production. In the future, the exploitation of gene editing approaches for in-vivo disease treatment may facilitate the resurgence of non-viral gene transfer approaches, which tend to be eclipsed by more efficient viral vectors.

show abstract

Section: A Brief History Of In-vivo Gene Therapymentioning

confidence: 99%

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

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

Self Cite

View full text Add to dashboard Cite

show abstract

“…The measured MMAD of pGM169/GL67A aerosols using the AeroEclipse ® II was 3.4 ± 0.1 µm, with a FPF of 71.4% ± 1.5%. 69 To confirm that nebulisation does not alter the ability of pGM169/GL67A to generate functional chloride channels, HEK-293T cells [American Type Culture Collection (ATCC), Teddington, UK] were transfected with pGM169/GL67A. The cells were collected prior to nebulisation and at the end of nebulisation (residual volumes in the nebuliser) and an iodide efflux assay, commonly used to assess CFTR function, was performed as previously described.…”

Section: Choice Of Nebuliser For Clinical Trial Programmementioning

confidence: 99%

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

Alton¹,

Armstrong²,

Ashby³

et al. 2016

Efficacy Mech Eval

Self Cite

View full text Add to dashboard Cite

BackgroundCystic fibrosis (CF) is a chronic, life-limiting disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene leading to abnormal airway surface ion transport, chronic lung infections, inflammation and eventual respiratory failure. With the exception of the small-molecule potentiator, ivacaftor (Kalydeco®, Vertex Pharmaceuticals, Boston, MA, USA), which is suitable for a small proportion of patients, there are no licensed therapies targeting the basic defect. The UK Cystic Fibrosis Gene Therapy Consortium has taken a cationic lipid-mediatedCFTRgene therapy formulation through preclinical and clinical development.ObjectiveTo determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF.DesignThis was a randomised, double-blind, placebo-controlled Phase IIb trial of theCFTRgene–liposome complex pGM169/GL67A. Randomisation was performed via InForm™ version 4.6 (Phase Forward Incorporated, Oracle, CA, USA) and was 1 : 1, except for patients in the mechanistic subgroups (2 : 1). Allocation was blinded by masking nebuliser chambers.SettingsData were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database.ParticipantsPatients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV1) between 50% and 90% predicted and any combination ofCFTRmutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised).InterventionsSubjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year.Main outcome measuresThe primary end point was the relative change in percentage predicted FEV1over the 12-month period. A number of secondary clinical outcomes were assessed alongside safety measures: other spirometric values; lung clearance index (LCI) assessed by multibreath washout; structural disease on computed tomography (CT) scan; the Cystic Fibrosis Questionnaire – Revised (CFQ-R), a validated quality-of-life questionnaire; exercise capacity and monitoring; systemic and sputum inflammatory markers; and adverse events (AEs). A mechanistic study was performed in a subgroup in whom transgene deoxyribonucleic acid (DNA) and messenger ribonucleic acid (mRNA) was measured alongside nasal and lower airway potential difference.ResultsThere was a significant (p = 0.046) treatment effect (TE) of 3.7% [95% confidence interval (CI) 0.1% to 7.3%] in the primary end point at 12 months and in secondary end points, including forced vital capacity (FVC) (p = 0.031) and CT gas trapping (p = 0.048). Other outcomes, although not reaching statistical significance, favoured active treatment. Effects were noted by 1 month and were irrespective of sex, age orCFTRmutation class. Subjects with a more severe baseline FEV1had a FEV1TE of 6.4% (95% CI 0.8% to 12.1%) and greater changes in many other secondary outcomes. However, the more mildly affected group also demonstrated benefits, particularly in small airway disease markers such as LCI. The active group showed a significantly (p = 0.032) greater bronchial chloride secretory response. No difference in treatment-attributable AEs was seen between the placebo and active groups.ConclusionsMonthly application of the pGM169/GL67A gene therapy formulation was associated with an improvement in lung function, other clinically relevant parameters and bronchial CFTR function, compared with placebo.LimitationsAlthough encouraging, the improvement in FEV1was modest and was not accompanied by detectable improvement in patients’ quality of life.Future workFuture work will focus on attempts to increase efficacy by increasing dose or frequency, the coadministration of a CFTR potentiator, or the use of modified viral vectors capable of repeated administration.Trial registrationClinicalTrials.gov NCT01621867.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.

show abstract

“…Thus this device was more efficient than other control devices in lung gene therapy for generating aerosol available for cystic fibrosis and for a range of acute and chronic diseased patients' inhalation [75].…”

Section: Other Diseasesmentioning

confidence: 98%

“…AeroEclipse II nebulizer formulated with pDNA complexed CLP like GL67A (pDNA/GL67A) for slower aerosol delivery only during the inspiratory phase was used as efficient lung gene therapy to many acute and chronic diseases, including cystic fibrosis as part of phase IIa/b clinical studies [75].…”

Section: Liposomal Nanomedicine: Preclinical and Clinical Studiesmentioning

confidence: 99%

Multidynamic Liposomes in Nanomedicine: Technology, Biology, Applications, and Disease Targeting

Ghosh

Ansar²

2014

Nanoparticles' Promises and Risks

View full text Add to dashboard Cite

Biocompatible and biodegradable liposome nanomedicine are finding large-scale application in delivery of drugs, RNA, antisense oligonucleotides, DNA, plasmids carrying gene, antioxidants to targeted sites for diagnosis, and treatment at cellular and molecular level of disease both in human and livestock.Conventional drug delivery system suffers from the disadvantage of narrow therapeutic index, poor serum solubility, and nonspecific target effects. Circumventing this problem, liposome drug nanoparticles are designed with the advantage of enhanced permeability, retention effect, selective targeted delivery, stimuli-induced release that can evade the host defense system, cross the bloodbrain barrier, thus conferring, synergetic effects, small interfering RNA (siRNA) co-delivery, multimodality therapies, and oral delivery of therapeutics at disease sites. Liposomes with diverse range of modifications are being designed to generate improvised medicine delivery systems. Immuno-liposomes, linked with antibodies are promising tools for targeted drug delivery to specific cancer cells. In the recent times several anti-cancer agents in nanodelivery systems are under preclinical and clinical studies. Lipid-based liposomal delivery systems of self-amplifying RNA vaccines are showing promising effects.Globally research is being carried out in generating liposomes with higher compatibility within the biological system in targeting a wide array of diseases including cancer, overcoming multidrug resistance, inflammatory diseases, thrombosis, psoriasis, muscular dystrophy, spinal cord injury, neurologic diseases, diabetes, parasite induced diseases, and cardiovascular diseases.

show abstract

Aerosol Delivery of DNA/Liposomes to the Lung for Cystic Fibrosis Gene Therapy

Cited by 47 publications

References 35 publications

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

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

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

Multidynamic Liposomes in Nanomedicine: Technology, Biology, Applications, and Disease Targeting

Contact Info

Product

Resources

About