Adeno-Associated Virus (AAV) gene therapy for cystic fibrosis: current barriers and recent developments

ABSTRACT

Introduction: Since the cystic fibrosis (CF) gene was discovered in 1989, researchers have worked to develop a gene therapy. One of the most promising and enduring vectors is the AAV, which has been shown to be safe. In particular, several clinical trials have been conducted with AAV serotype 2. All of them detected viral genomes, but identification of mRNA transduction was not consistent; clinical outcomes in Phase II studies were also inconsistent. The lack of a positive outcome has been attributed to a less-than-efficient viral infection by AAV2, a weak transgene promoter and the host immune response to the vector.

Areas covered: Herein, the authors focus on AAV gene therapy for CF, evaluating past experience with this approach and identifying ways forward, based on the progress that has already been made in identifying and overcoming the limitations of AAV gene therapy.

Expert opinion: Such progress makes it clear that this is an opportune time to push forward toward the development of a gene therapy for CF. Drugs to treat the basic defect in CF represent a remarkable advance but cannot treat a significant cohort of patients with rare mutations. Thus, there is a critical need to develop a gene therapy for those individuals.

KEYWORDS:

• Gene therapy
• cystic fibrosis
• adeno-associated virus
• preclinical testing
• clinical trials

Article highlights

• Since the cystic fibrosis gene was discovered in 1989, researchers have worked to develop a gene therapy as an ultimate cure.

• One of the most promising and enduring vectors is the adeno-associated virus (AAV), which has been shown to be safe in several clinical trials.

• A number of preclinical studies were performed to demonstrate the safety, efficacy of transduction, and long-term expression of AAV; all provide a solid foundation upon which to move toward a clinical therapy.

• An initial phase of clinical studies of AAV in CF patients were similar in that vector genomes were detected and in one instance there was functional rescue of CFTR function but no sustained clinical outcome was noted with first generation vectors.

• The limitations of initial AAV gene therapy studies are well known and strategies to surmount them are well underway.

• With many new AAV serotypes available and new promoters to drive CFTR expression the field of CF gene therapy is again at the forefront.

This box summarizes key points contained in the article.

Acknowledgments

The authors wish to thank Dr. Deborah McClellan for editing the manuscript.

Declaration of interest

WB Guggino has a consultant agreement with the Vertex Corporation while L Cebotaru has a license agreement with Vertex for mutant cell lines. L Cebotaru also has a contract with Acetylon Pharmaceuticals to investigate a HDAC6 inhibitor unrelated to this review. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors are funded by NIH grant R01 HL122267 and grant GUGGIN14P0 from the Cystic Fibrosis Foundation.