Gene Therapy in Rare Respiratory Diseases: What Have We Learned So Far?

Abstract

Gene therapy is an alternative therapy in many respiratory diseases with genetic origin and currently without curative treatment. After five decades of progress, many different vectors and gene editing tools for genetic engineering are now available. However, we are still a long way from achieving a safe and efficient approach to gene therapy application in clinical practice. Here, we review three of the most common rare respiratory conditions—cystic fibrosis (CF), alpha-1 antitrypsin deficiency (AATD), and primary ciliary dyskinesia (PCD)—alongside attempts to develop genetic treatment for these diseases. Since the 1990s, gene augmentation therapy has been applied in multiple clinical trials targeting CF and AATD, especially using adeno-associated viral vectors, resulting in a good safety profile but with low efficacy in protein expression. Other strategies, such as non-viral vectors and more recently gene editing tools, have also been used to address these diseases in pre-clinical studies. The first gene therapy approach in PCD was in 2009 when a lentiviral transduction was performed to restore gene expression in vitro; since then, transcription activator-like effector nucleases (TALEN) technology has also been applied in primary cell culture. Gene therapy is an encouraging alternative treatment for these respiratory diseases; however, more research is needed to ensure treatment safety and efficacy.

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.…”

Updates in the Management of Alpha-1 Antitrypsin Deficiency Lung Disease

“…Lungs are a promising organ for gene therapy, since the vector can be delivered directly via nebulization, pleural administration or intramuscular administration; however, challenges include the barrier posed by the mucus lining of the airway epithelium, which can trap vectors, and the relatively rapid renewal of the epithelial cells requiring repeated therapeutic administration. 73 Adeno-associated viral (AAV) vectors, considered safer than other types of vectors because they do not integrate into the genome, were first used in AATD gene therapy. 73 In a phase I clinical trial, recombinant AAV serotype 2 vector expressing AAT (rAAV2-AAT) was administered via intramuscular injection in 12 patients with AATD.…”

“…73 Adeno-associated viral (AAV) vectors, considered safer than other types of vectors because they do not integrate into the genome, were first used in AATD gene therapy. 73 In a phase I clinical trial, recombinant AAV serotype 2 vector expressing AAT (rAAV2-AAT) was administered via intramuscular injection in 12 patients with AATD. The therapy yielded low levels of wild-type AAT, with the emergence of anti-rAAV2 antibodies.…”

CRISPR/Cas: a Nobel Prize award-winning precise genome editing technology for gene therapy and crop improvement

“…However, ZFNs recognize C2–H2 domains, whereas TALENs recognize DNA through transcription activator-like effectors (TALEs) ( Baker, 2012 ). Although both ZFNs and TALENs have been well used to target and edit specific genes, with some applications in clinical treatments ( Ellis et al, 2013 ; Xu et al, 2014 ; Aravalli and Steer, 2016 ; Bañuls et al, 2020 ), they both have some shortcomings for genome editing. Like meganucleases, engineering ZFNs and TALENs to target desired sequences can be time-consuming, and often requires specialist knowledge ( Table 1 ).…”