Microenvironment Modifying Delivery of Alpha-1-Antitrypsin


Inventors are designing a targeted nanocarrier to be used to deliver and protect alpha-1-antitrypsin (A1AT) for the initial therapy of emphysema. The device will be engineered in such a way as to have a protective anti-oxidant coat/shield to prevent the oxidative modification of alpha-1-antitrypsin by the extracellular or intracellular microenvironment. As part of the novel design, A1AT will be contained within a core of a liposome surrounded by an anti-inflammatory therapeutic and coated as described above with an FDA approved anti-oxidant. This technology, while designed specifically for emphysema, has broader application to all acute and chronic lung diseases, transplantation, ischemia reperfusion injury, and autoimmune disorders.

Overview: Chronic obstructive pulmonary disease (COPD) is a smoking-related disorder that by 2020 is predicted to be the 3rd leading cause of death worldwide. The single most important factor in the development of emphysema is cigarette smoke. Several mechanisms have been postulated to contribute to the pathogenesis of emphysema, with perhaps the best characterized being the protease anti-protease hypothesis. This arose from observations that patients with a genetic deficiency in alpha-1-antitrypsin (A1AT), the major serine protease inhibitor present in the lung, were predisposed to the early development of emphysema, which was further exacerbated in patients if they were cigarette smokers. In addition to the protease anti-protease hypothesis a number of other mechanisms have been proposed, such as, the oxidant anti-oxidant hypothesis. Central to all of the proposed mechanisms is an imbalance in the lung’s protective defenses, which become overwhelmed by excessive activation of systems that can induce inflammation, damage and disease.

The central link to all these hypothesized mechanisms is oxidative stress. Oxidative stress not only causes lung inflammation, but further oxidatively inactivates alpha-1-antitrypsin, resulting in a functional deficiency in A1AT in patients that do not have the genetic deficiency. Therapies for emphysema are sparse with the only available therapies being bronchodilators and steroids. These have limited efficacy, and in the case of steroids, oxidative stress, which persist even following smoking cessation, reduces steroid receptor expression and thus reduces steroid efficacy.

In recent years intravenous alpha-1-antitrypsin (A1AT) augmentation therapy has been employed to restore A1AT in deficient patients (Z-A1AT). Restoration of physiological concentrations of A1AT in these patients is thought to restore protection of the lungs from neutrophil elastase, and hence slow the aggressive form of emphysema seen in these patients. This approach could undoubtedly benefit all emphysema patients, however the high cost associated with intravenous therapy has prohibited its large-scale implementation. Despite these cost barriers, a strong rationale for augmenting nongenetic deficient emphysema patients (M-A1AT) has begun to attract attention. These normal emphysema patients (M-A1AT) are not systemically deficient in A1AT, but have a local lung ‘functional’ deficiency induced by oxidative modification of A1AT by cigarette smoke exposure and ROS generated by the increased lung inflammatory burden seen in these patients. This ‘functional’ deficiency renders patients prone to protease-mediated injury similar to that seen in Z-A1AT. Therefore, augmenting M-A1AT patients locally (directly into the lungs) may go a long way in restoring this protease anti-protease imbalance induced by oxidative inactivation.

Applications: Therapy for respiratory illness such as emphysema as well as all acute and chronic lung diseases, transplantation, ischemia reperfusion injury, and autoimmune disorders

Advantages: Delivery device allows for protection of A1AT and localized delivery

Key Words: Emphysema, lung, liposome, drug delivery, alpha-1-antitrypsin, respiratory illness

Inventors: Carl Atkinson, Ann-Marie Broome, Satish Nadig
Patent Status: PCT Application (WO2016179365) published 05/05/2016
MUSC-FRD Technology ID: P1536

Patent Information:
For Information, Contact:
Scott Davis
Sr Licensing Manager
MUSC Foundation for Research Development
Carl Atkinson
Ann-Marie Broome
Satish Nadig
© 2017. All Rights Reserved. Powered by Inteum