A novel anti-infective approach is to exploit stresses already imposed on invading organisms in vivo. Iron (Fe) metabolism is a key vulnerability of infecting bacteria because organisms require Fe for growth. We have shown that a strategy that uses the metal gallium (Ga) to disrupt bacterial Fe, metabolism holds promise as an antimicrobial approach. Due to its chemical similarity to Fe, Ga can substitute for Fe in many biologic systems and inhibit Fe-dependent processes. Our data shows that Ga kills the opportunistic pathogen Pseudomonas aeruginosa (including antibiotic resistant strains), is active against biofilms, and treats 3 different models of P. aeruginosa infections. Ga has also been shown to have anti-inflammatory properties. These data, the fact that gallium nitrate (trade name, GaniteTM) is Food and Drug Administration (FDA) approved for intravenous (IV) administration, and the dearth of new antibiotics in development make Ga a promising new therapeutic for P. aeruginosa infections. We have shown in our initial phase 1b study in patients with cystic fibrosis chronically infected with P. aeruginosa that IV Ga is safe, well tolerated, ha a good pharmacokinetic profile and is associated with a clinically meaningful improvement in lung function 14 days and 28 days after the start of a 5 day infusion of IV Ga. Here we propose a proof of concept phase 2 clinical trial to confirm our prior findings of efficacy and provide further data regarding the safety and pharmacokinetics of IV Ga in CF subjects infected with P. aeruginosa. We also propose two ancillary projects to further delineate the mechanism of action of this new agent. Chronic P. aeruginosa airway infections are the major cause of death in these patients and few treatments exist. This drug could represent a novel approach to treating this infection and have implications for other challenging infections.
P. aeruginosa accounts for approximately 60% of the chronic lung infections in patients with cystic fibrosis (CF), an orphan disease, and ~ 90% of deaths are attributed to chronic airway damage caused by this organism. We have also shown that Ga is safe and well tolerated in our phase 1 b study in CF with preliminary evidence of clinical efficacy. We propose to assess efficacy of Ga in a proof of concept randomized controlled trial in adults with CF chronically infected with P. aeruginosa.
|Goss, Christopher H; VanDevanter, Donald R (2016) CFTR modulators and pregnancy: Our work has only just begun. J Cyst Fibros 15:6-7|
|Heltshe, Sonya L; Goss, Christopher H (2016) Optimising treatment of CF pulmonary exacerbation: a tough nut to crack. Thorax 71:101-2|
|Crull, Mathew R; Ramos, Kathleen J; Caldwell, Ellen et al. (2016) Change in Pseudomonas aeruginosa prevalence in cystic fibrosis adults over time. BMC Pulm Med 16:176|
|Ramos, Kathleen J; Quon, Bradley S; Psoter, Kevin J et al. (2016) Predictors of non-referral of patients with cystic fibrosisfor lung transplant evaluation in the United States. J Cyst Fibros 15:196-203|
|Sack, Cora S; Goss, Christopher H (2016) Nature versus Nurture: Does Genetic Ancestry Alter the Effect of Air Pollution in Children with Asthma? Am J Respir Crit Care Med 193:1196-8|
|Ramos, Kathleen J; Goss, Christopher H (2015) Remarkable long-term survival post-lung transplantation among Canadian patients with cystic fibrosis. J Heart Lung Transplant 34:1131-3|
|Goss, Louisa B; Ortiz, Justin R; Okamura, Daryl M et al. (2015) Significant Reductions in Mortality in Hospitalized Patients with Systemic Lupus Erythematosus in Washington State from 2003 to 2011. PLoS One 10:e0128920|
|Sack, Coralynn; Goss, Christopher H (2015) It Starts at the Beginning: Effect of Particulate Matter In Utero. Am J Respir Crit Care Med 192:1025-6|
|Abdalla, Maher Y; Switzer, Barbara L; Goss, Christopher H et al. (2015) Gallium Compounds Exhibit Potential as New Therapeutic Agents against Mycobacterium abscessus. Antimicrob Agents Chemother 59:4826-34|
|Goss, Christopher H; MacNeill, Stephanie J; Quinton, Hebe B et al. (2015) Children and young adults with CF in the USA have better lung function compared with the UK. Thorax 70:229-36|
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