Origins & Discovery

1960 – 2013: The 50th Anniversary of the Discovery of Alpha-1 Antitrypsin Deficiency

A Viking Legacy

Origins

Alpha-1 Antitrypsin Deficiency (AATD) is often referred to as the “Viking Legacy”. It is believed that the “Z” mutation originated from a single source 66 generations (approximately 2,000 years) ago in southern Scandinavia, where the mutation has the highest frequency. Migration patterns that show how the mutation was dispersed across Northern Europe between 700 and 1000 A.D. match the areas of Viking conquests. It is therefore believed that Viking migration spread the “Z” mutation.

The “S” mutation is much older and is believed to have originated in the Iberian Peninsula. The date of this is uncertain, but similarly to the “Z” mutation, the “S” mutation was introduced to the rest of the World through migration.

Discovery

Alpha-1 Antitrypsin Deficiency (AATD) was first reported in 1963 by Carl-Bertil Laurell and Sten Eriksson, who discovered a link between low blood levels of alpha-1 antitrypsin (AAT) and symptoms of pulmonary emphysema. Since this discovery, an understanding of the biomechanical mechanisms and genetic abnormalities involved has developed, and AATD is now thought to be one of the most common hereditary disorders worldwide, comparable in frequency to cystic fibrosis. By 1969, an association with liver disease had been discovered in the US, and patients in both Europe and North America began to be identified with the condition.

Scandinavian Viking Invasion and Settlement 700 to 1000 AD

The Viking invasion began at the end of the eighth century AD, with England, the rest of the British Isles, and Ireland soon following. Early settlement began in Ireland (840s AD). As they established themselves in Great Britain and Ireland, which they dominated through the eleventh century, it prepared them to explore lands further west. On their way, they discovered the Faroe Islands and Iceland in the mid-ninth century, and in 900 AD, they found Greenland. Their most intriguing discovery was that of North America around 1000 AD, where they initially thought it was just another island. They named it Vinland due to the world vines that grew, which produced fine wine.

While the Norwegian Vikings were exploring the west, the Danish Vikings set out for the south, attacking Aquitaine (799 AD), Spain (814 AD) and France, taking Paris (845 AD). The Vikings’ adventures into Eastern Europe were primarily trade-related, where they established trade routes along Russian rivers such as the Volga and the Dnieper.

The cause of the Viking expansion is unknown. However, it has been suggested that overpopulation in Scandinavia forced many Vikings to seek their fortunes in other lands; some became traders, and some became invaders.

Alpha-1 Antitrypsin Deficiency Prevalence Worldwide

116 million MZ and MS
3.4 million SZ, SS and ZZ

In a total population of 4.4 billion in the 58 countries surveyed, there are at least 116 million carriers of defective genes (those with Pi phenotypes PiMS and PiMZ) and 3.4 million with deficiency allele combinations (phenotypes PiSS, PiSZ, and PiZZ) for the two most prevalent deficiency alleles PiS and PiZ, which suggests that AATD may be one of the most common serious single-locus genetic diseases in the world.

Source: Alpha-1 Antitrypsin Deficiency is Not a Rare Disease but a Disease That is Rarely Diagnosed, Frederick J. De Serres, December 2003, Environmental Health Perspectives: Dec 2003, Vol 111, Issue 16, p1851

Alpha-1 Antitrypsin Deficiency: Origins and Discovery

Alpha-1 Antitrypsin Deficiency: Where are we now?

In the 1980s, Gadek and colleagues developed augmentation therapy, also known as replacement therapy, in which the alpha-1 antitrypsin (AAT) protein is isolated from human blood serum and administered intravenously to increase the AAT concentration circulating in the blood. The intended outcome of augmentation therapy is to protect against the accelerated decline in lung function experienced by individuals with AAT deficiency. Augmentation therapy has been approved in 20 countries worldwide, including the USA and Canada, as well as thirteen in Europe: Germany, Spain, Austria, Italy, Belgium, and France. Many other countries, including the UK, Sweden and Australia, are still awaiting proof of clinical efficiency before licensing. Augmentation therapy is not indicated in individuals who have partial AAT deficiency (MZ heterozygotes) or in patients with AATD associated liver disease.

More recently, inhaled AAT therapy has been developed, which aims to replenish AAT in lung tissue through direct inhalation.

Initial studies indicate that this may provide sufficient AAT to reach normal concentrations in the lung fluid. Clinical trials are now in advanced stages, with interim reports demonstrating an excellent safety and tolerability profile of the product. The product is currently under FDA and EU Orphan Drug Designation.

Exciting new developments combining Gene Therapy and Stem Cells have been realised, where patients with genetic diseases could one day be treated with their own cells. A team of researchers has corrected a faulty gene in induced pluripotent stem (iPS) cells derived from skin cells of people with AAT metabolic liver disease. The researchers then developed the stem cells into something resembling liver cells. Researchers said this was a “critical step” towards devising treatments, but safety tests were still needed. If this could be developed into a therapy, it would be preferable to a liver transplant, as the patient would not need to take immunosuppressant drugs. Trials are currently in Phase I in a first in human study.

• Alleles

  Different versions of the same gene, inherited one from each parent, that determine specific traits.

• Alpha-1 Antitrypsin (AAT)

  A protein produced primarily in the liver that protects the lungs from damage, and other inflammation, by controlling enzymes like proteases.

• Alpha-1 Antitrypsin Deficiency (AATD)

  A genetic condition where the body doesn’t make enough AAT, or produces abnormal AAT that accumulates in the liver, leading to lung and/or liver disease.

• Biomechanical

  The application of mechanical principles to biological systems, studying how forces affect structure, function, and motion.

• Cystic Fibrosis

  A hereditary disorder causing abnormally thick mucus, blocking ducts in the pancreas, intestines, and lungs, often leading to infections.

• DNA (Deoxyribonucleic Acid):

  A molecule that carries the genetic instructions for development, function, and reproduction for living organisms.

• Electrophoresis

  A lab technique using an electric field to separate charged molecules (DNA, RNA, proteins) through a gel, forming distinct bands for analysis.

• Emphysema

  A progressive lung disease where alveoli (air sacs) are damaged, reducing surface area for gas exchange and trapping air, causing shortness of breath.

• Gene

  An inherited part of DNA that provides the instructions for making a specific molecule within the body, such as a type of protein.

• Gene Therapy

  A medical approach that modifies genes to treat or prevent disease by correcting, replacing, or adding genetic material.

• Genotype

  The specific variants of alleles and individual carries within their gene.

• Heredity (Inheritance)

  The passing of traits from parents to offspring through genetic information, via reproduction.

• Heterozygote

  An individual with two different alleles of a particular gene, which may lead to varying traits in offspring.

• Immunosuppressant

  A drug that suppresses or reduces the activity of the immune system.

• Induced Pluripotent Stem Cells (iPSCs)

  Adult cells reprogrammed to an embryonic-like state, capable of differentiating into nearly any cell type.

• Inhalation

  The act of breathing in air.

• Metabolic Liver Disease (AATD-related)

  A complication of AATD where abnormal protein accumulates in the liver causing damage.

• Orphan Drug Designation

  A status granted to drugs developed for rare diseases, providing financial, regulatory, and market incentives to encourage treatment development.

• PI Phenotype / Genotype

  Refers to genetic variations in the SERPINA1 gene.

  • PiMM: Normal AAT levels
  • PiMS: Carrier of one deficient gene, reduced levels
  • PiMZ: Carrier of one deficient gene, reduced levels
  • PiSS: Moderate deficiency
  • PiSZ: Moderate deficiency
  • PiZZ: Severe deficiency
• Phenotype

  The observable characteristics expressed by an individual’s genotype. and environment.

• Protease

  An enzyme that breaks down proteins.

• Pulmonary

  Relating to the lungs.

• S Mutation (PI*S)

  A SERPINA1 gene variant that results in moderately low levels of AAT. Usually sufficient to protect the lungs, but risk increases when combined with other factors such as smoking.

• SERPINA1 gene

  The gene that provides the instructions for making the AAT protein in the body.

• Stem Cells

  Undifferentiated cells capable of developing into many different specialized cell types.

• Z Mutation (PI*Z)

  A variant of the SERPINA1 gene that causes misfolded AAT to build up in the liver, severely reducing the amount available in the lungs.