The Alpha-1 Project will consider all opportunities which have a strong potential to result in a therapy or device to eliminate the effects of COPD and liver disease caused by Alpha-1 Antitrypsin Deficiency. However, based on our current understanding of the molecular mechanisms underlying Alpha-1 related lung and liver disease, The Alpha-1 Project’s initial scientific focus will be on the search for small molecules and chaperones to correct the basic defect in cellular alpha-1 antitrypsin (AAT) trafficking and polymerization, the development of new molecules with anti-elastase activity, and gene/stem cell therapies.

The lung disease of Alpha-1 is primarily related to an imbalance between injurious agents that are damaging the lungs and the protective mechanisms that protect normal lung tissue from injury. Because elastase released from the human neutrophilic white blood cell has been implicated as the primary injurious agent that leads to lung tissue destruction in Alpha-1, it is logical to seek therapeutic compounds that inhibit this elastase activity. While AAT is an excellent elastase inhibitor, current therapy with intravenous plasma derived AAT purified from healthy donors has many drawbacks. Therefore, attention has turned toward synthesizing small molecule inhibitors of elastase. These agents have the potential to be given by inhalation or even by oral administration as a pill. Anti-elastases would be expected to halt or prevent proteolytic injury to lung tissue and could have a role in protecting other connective tissues damaged by inflammation due to neutrophil white blood cells. A number of companies have made good pre-clinical progress in this area.

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A series of investigations has clarified various steps involved in the hepatotoxicity of ZZ AAT misfolding, including the protein’s abnormal intracellular trafficking, accumulation and degradation in the ER, and the processes of apoptosis and autophagy that lead to liver cell death. Similar processes and an upregulation of the unfolded protein response are likely to occur in lung cells as alveolar macrophages and lung epithelial cells also synthesize AAT. In Alpha-1 Antitrypsin Deficiency (Alpha-1) the misfolded ZZ AAT that is made in the lung could contribute to lung cell apoptosis, a recognized feature of Chronic Obstructive Pulmonary Disease (COPD). Thus, several new drug targets have emerged that could be tested by high throughput technology involving relevant cell systems and subsequently validated in animal models and human subjects.

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Gene Therapy

As a genetic condition, it is reasonable to consider treating Alpha-1 with gene therapy. Currently, a number of approaches are being evaluated. These include inserting the normal AAT gene into accessible cells such as muscle or bronchial cells, inserting the normal AAT gene into liver cells (the usual site of synthesis of AAT), and inserting genetic agents that “turn off” production of abnormal AAT in the liver. The first approach is already moving forward into early phase human trials with one particular vector. Recent reports have suggested the second approach may have merit as well. If one is looking to prevent the liver disease of Alpha-1, the third approach may be the most direct.

Stem Cell Therapy

Stem cell therapy, or therapy that employs undifferentiated cells to repair or replace mature tissues or organs, is currently in its infancy, especially with respect to Alpha-1. Stem cells are very primitive, undifferentiated cells and usually do not express proteins that cause a normal individual to recognizing them as “foreign.” Therefore, tissues derived from these cells may not be rejected when administered to a patient. In Alpha-1, research is looking toward repairing the liver or lung using stem cells derived from a variety of sources. Potentially, administering these cells to a damaged liver or lung could promote repair to the defects that are caused by having Alpha-1.

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The Alpha-1 Project will focus on developing devices to assist in the treatment and monitoring of persons with COPD and liver disease caused by Alpha-1. It also considers improvements in the early detection of the condition to be a high priority.

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If you are interested in receiving support for a research project that falls into one of the categories listed on our Therapeutic Strategies, please follow the application instructions.

Click to download: Letter of Interest and Full Application Instructions

Thank you for your interest in ending the effects of COPD and liver disease caused by Alpha-1 Antitrypsin Deficiency.

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