A non-pathogenic strain of Burkholderia cepacia provides an opportunity to develop a live vaccine to prevent Bcc infection in CF and critically ill patients, which would dramatically improve the quality of life and life expectancy of these patients.

Keywords: antibiotic resistance, bacteria, Burkholderia, chronic lung disease, Cystic Fibrosis, immune compromise, immunization, molecular tool, mutagenesis, pathogenesis, respiratory infections, screen, vaccine

DESCRIPTION OF THE INVENTION: A growing body of clinical evidence has raised awareness of the infectious risk that is posed by the Burkholderia cepacia complex (Bcc) particularly with respect to infection of Cystic Fibrosis (CF) or other critically ill patients. The present invention relates to a novel mutagenesis system that will enable the creation of unmarked (i.e. no foreign material is integrated into the genome as a result of the mutagenesis procedure) and targeted deletions in Bcc. Proof of principle studies have been conducted and have demonstrated that multiple mutations can now be made within the same bacterial cell - a feat not previously possible. These new tools make it possible to engineer non-pathogenic Burkholderia species that are ideally suited for the development of live vaccines for immunization of CF patients or others at risk.

BACKGROUND: CF is a progressive and fatal genetic disease of the exocrine glands that affects the sweat glands and the respiratory and digestive systems primarily of infants, children, and young adults. The incidence of the disease is approximately 1 in 20,000 worldwide and affected individuals have a life expectancy of only 29-31 yrs in most countries. The most prevalent complications of CF are chronic respiratory infections that develop as a result of thick mucus obstructing the airways, which proves fatal in many cases.

Bcc is a group of nine bacterial species within the genus Burkholderia that are found in a variety of natural habitats including plant rhizospheres, soil, river water, and urban environments. Bcc respiratory infection has been found to have a prevalence of 5 - 25% in CF patients. Even though Bcc infection is often a secondary infection to Pseudomonas aeruginosa, the proportional hazard for severe clinical decline is substantially increased following infection with Bcc. Studies have demonstrated that the mean survival of CF patients decreases by ~10yrs in the Bcc-culture positive population compared with the P.aeruginosa-positive population. A devastating drawback to Bcc infection is that it limits the selection of these CF patients for lung transplantation because of the high risk of post-operative sepsis and death. Current treatment regimens using antibiotics is often ineffective for Bcc infections due to their resistance to many commonly used antibiotics. Vaccination may prove an effective strategy for preventing Bcc infection.

POTENTIAL ADVANTAGES/USES:

• Enables production of non-pathogenic strains of Bcc
• Potential to develop a live vaccine to prevent Bcc infection in high risk patients
• Capacity to identify the mechanisms of Bcc antibiotic resistance and generate targets
• Mechanism of mutagenesis does not involve the introduction of foreign DNA
• Genomic sequence of Bcc is publicly available for targeted deletions

Ref. #: UWO-AI-021

Preclinical

DEVELOPMENTAL STAGE: Proof of principle

PATENT INFORMATION: US provisional patent application filed

Available for license and/or collaborative approach