Can neonatal exposure improve the effectiveness of cystic fibrosis gene therapy re-dosing?

Chief Investigator: Dr Nigel Farrow

Funding Amount: $34,624

Recipient: University of Adelaide


The lung grows and its cells turn over numerous times throughout a person’s lifetime; this continual self-renewal can limit the longevity of gene therapies targeting the lung, leading to the need for re-dosing. Since immunological responses are known to reduce the re-dosing potential of gene therapies, we will assess the theory that neonatal exposure to gene therapy can promote tolerisation, thereby improving the efficacy of re-administered gene therapy later in life. This study will help verify that very early gene therapy initiation is a justified course of action to prevent lung disease in infants with cystic fibrosis.

Research Outcomes:

Researchers: Dr Nigel Farrow, Dr Martin Donnelley, Dr Patricia Cmielewski, Dr Juliette Delhove, A/Prof David Parsons

Research Completed: 2021

Research Findings: Gene therapy has great potential for correcting the disease in the lungs of patients with Cystic fibrosis. We have previously demonstrated a proof of principle for our airway gene therapy treatment developed in South Australia. To improve the consistency and levels of response to the treatment we performed a pilot study to determine if a gene therapy treatment given in the first days after birth is feasible and if it led to a more consistent and reliable outcome both from the initial dose and subsequent adult redosing of the treatment.

Key Outcomes:

Gene therapy has shown potential to treat or prevent cystic fibrosis (CF) airway disease by delivering a functional CFTR gene into airway epithelial cells. Our two-step dosing protocol conditions the airway prior to gene therapy delivery, however achieving consistent high and sustained levels of gene expression remains challenging. To maintain therapeutic benefit over a lifetime, re-dosing may be necessary.

The aim of this pilot project was to determine if delivery of a LV vector during neonatal development soon after birth, could establish reliable and/or higher levels of initial transgene expression and from subsequent adult gene therapy dosing.

The nasal airways of neonatal (3 day old) rats were treated with gene therapy or a sham control. imaging of the rats was performed 6 weeks post neonatal gene therapy dosing to assess nasal initial transgene expression. The chest was also imaged to determine if the nasal dose had infiltrated the lung regions. One week following these assessments, these now adult animals received an airway-conditioning treatment followed by an adult gene therapy treatment, delivered by bronchoscopy into the right main bronchus, and examination was again performed one week later to assess transgene expression. Blood samples were obtained before and after the gene therapy treatment for analysis of immune response to the transgene and vector pseudotype.

Expression of the inserted gene was detected 6 weeks post neonatal vector dose in the nasal airways of all animals in the treatment group, but not in any controls. One week after adult rat gene therapy dosing, gene expression remained: in the nasal airways of all neonatal LV-treated rats; in the lungs of 10 of 11 animals; and in the lungs of 6 of 10 control animals. Analysis of blood serum taken before and after the gene therapy treatments showed there was no immune response to the transgene or vector pseudotype. Our results suggest that this form of neonatal dosing did not increase overall acute lung gene therapy expression levels. However, the number of responders in the neonatal treatment group compared to the control group suggests that the treatment of gene therapy at a neonatal age may result in a more reliable outcome of successful transgene expressing animals and future studies with a larger sample size are required to determine this. Future studies will also be required to assess a broader range of immune responses to determine if neonatal gene therapy dosing has a preventative impact on immune responses to the treatment.

Research Papers:

An abstract was submitted to the North American Cystic Fibrosis Foundation Conference to be held in San Antonio, Texas in September 2021. I am pleased to say that the abstract was accepted for a poster presentation, and I was also invited to give a talk to present the study at the conference. I have accepted both the poster and oral presentations. Copies of the presentations will be sent when they have been finalised. A manuscript to be submitted for peer review publication is currently being prepared. All presentations and manuscripts will acknowledge the funding support provided by the CRF.

Related Publications:

Future Outcomes:

Leave a Reply