This proposal describes a novel strategy to treat emphysema in COPD (chronic obstructive pulmonarydisease) using uniquely tailored heparan sulfate produced from genetically engineered mammalian cells.Emphysema is a major component of COPD, a disease that afflicts up to 5% of the population and is the 4thleading cause of death in the US. There is currently no drug that has proven efficacious to cure or delayprogression of the disease. While targeted therapies have shown little clinical benefit, heparin has multi-pointinhibitory activity against the three major drivers of disease progression (proteases, oxidative stress andinflammation) and can be inhaled for local treatment. Heparin's usefulness is limited by its anticoagulantactivity. TEGA Therapeutics' recombinant heparan sulfate production technology enables targeted eliminationof 3-O-sulfate groups that are essential for anticoagulant activity while maintaining anti-elastolytic, anti-oxidative and anti-inflammatory properties. Mammalian cell lines that produce heparan sulfate without 3-O-sulfate will be genetically engineered to improve inhibition of emphysema drivers. The products will then betested to evaluate their ability to inhibit proteases, oxidative stress and inflammatory mediators in vitro. Finally,the efficacy of the top candidate will be assessed through orotracheal delivery in a rat model of emphysema.The resulting product will be further developed as an inhalable drug in Phase II through bioprocessdevelopment, formulation, toxicology studies and pharmacokinetic studies. Success in this endeavor will yielda clinical drug that limits the progression of emphysema and increases the duration and quality of life forpatients. It would likely also be useful for other chronic pulmonary diseases including cystic fibrosis and alpha-1 antitrypsin deficiency.
Public Health Relevance Statement: PROJECT NARRATIVE
Emphysema/COPD is the 4th highest cause of death in the US and there is no drug that reverses or
delays the progression of the disease. This project will develop a recombinant heparan sulfate that
inhibits multiple mechanisms of emphysema progression and will demonstrate its efficacy by local
delivery in an animal model of emphysema. Success in this endeavor will lead to further drug
development for a novel inhaled therapy to treat patients with emphysema.
Project Terms: <α-1 anti-trypsin deficiency><α-1-antitrypsin deficiency><α1-Antitrypsin Deficiency>|
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