Alpha-1 Antitrypsin Deficiency (Alpha-1) is a genetic/hereditary condition that leads to decreased circulating levels of alpha-1 antitrypsin (AAT) and significantly increases the risk of serious lung disease in adults and liver disease in infants, children and adults. Over 100 abnormal alleles have been identified for the AAT gene and of these about 1/3 are known to cause deficiency. The most common abnormal genes are the S and Z alleles, named according the speed of migration in an isoelectric focusing gel. Normal genes are labeled M (e.g.: M1, M2, M3, M4). Some abnormal alleles lead to a non-translatable gene product and therefore produce no AAT, these are the Null alleles. The most common genotype associated with Alpha-1 is ZZ (also referred to as PiZ). There are about 100,000 people with the ZZ phenotype in the US although less than 10% have been detected to date. Another deficient gene combination is SZ. Statistically SZ should be more common in the US than ZZ, however, since people with SZ are less likely to get lung or liver problems than those with two Z genes, fewer individuals with SZ have been identified.

Diseases most commonly associated with Alpha-1:

• Emphysema
• Chronic bronchitis
• Bronchiectasis
• Chronic Obstructive Pulmonary Disease (COPD)
• Cirrhosis
• Neonatal hepatitis
• Hepatocellular carcinoma
• Necrotizing panniculitis
• Non-tuberculous mycobacterial infection
• Increased risk of chronic/chronic active hepatitis

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Since its inception in 1996, the stated goal of the Alpha-1 Foundation’s research program was to better understand the biological link between the genetic defect and phenotypic manifestation of Alpha-1. Early on, it was recognized that a multidimensional approach would best serve this goal. Thus, three separate but interrelated programs were created to promote basic and clinical research under the oversight of the Foundation’s Medical and Scientific Advisory Committee and administered by experienced staff with advice from a Scientific Director. The program’s three major pillars have been a peer-reviewed research grant program, a DNA and Tissue Bank and a Research Registry, with the expectation that the latter two would be valuable resources for investigators within and outside the US that are otherwise not available.

An analysis of the research program’s productivity and its impact on our current understanding of the biology of Alpha-1 shows that the Foundation has succeeded in its quest to bring us closer to new therapeutic solutions and the cure of Alpha-1. The research conducted to date, to a great extent supported by the Foundation’s research grants and related programs (over $40 million), has clarified the mechanism of Alpha-1 disease and identified novel therapeutic targets. With our better understanding of the processes underlying Alpha-1-related diseases, and new technological advances, the Foundation is now in a position to promote more targeted research. Future research dollars will be increasingly directed towards this targeted research that would not be possible without the many academic investigators whose discoveries have brought the field to this critical juncture.

Today we know the genetic mutations responsible for the unfolded alpha-1 antitrypsin protein (AAT), generally understand how the unfolded AAT polymerizes and leads to cellular processes that injure the liver and the lung (gain of function), and how the defect in AAT secretion into the blood circulation can expose the lung to the elastolytic actions of neutrophil elastase and other serine proteases, and the development of COPD (loss of function). Of the 99 grants awarded by the Foundation to scientists in and outside the US, 55 addressed the pathogenesis of Alpha-1, 22 were clinical studies, and 24 dealt with novel therapeutic solutions, with overlaps in some of the investigations.

An encouraging conclusion that can be drawn from the review of this research activity is that it has identified new targets for therapeutic interventions with the potential of controlling or curing the liver and lung disease of Alpha-1. These investigations will be directed at finding novel drugs, and gene-and cell-based interventions that target the basic defect in Alpha-1; academia, biotechnology and traditional pharmaceutical companies are best suited for this and the Foundation now has established The Alpha-1 Project to promote this kind of research. The hope is that the new drugs will benefit not only patients with Alpha-1 Antitrypsin Deficiency but also a large population with generic COPD.

More information on the symptoms of Alpha-1 Antitrypsin Deficiency and its effects can be found at www.alpha-1foundation.org.

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