Alpha-one Antitrypsin Deficiency Liver Disease

These images show mouse livers where individual hepatocytes can be identified. The brown color represents presence of Z-AAT. On the left is the liver of an untreated PiZ mouse. On the right is the liver of a PiZ mouse that was treated with our silencing gene therapy vector, where staining is visibly reduced.

What is alpha-one antitrypsin (AAT) deficiency liver disease?

AAT deficiency occurs worldwide, but the prevalence is variable depending on regions. It is a rare disease in Europe and in the US. It affects between 1:1500 and 1:3500 in people of European descent. It is the 2nd most common genetic disorder in Ireland, where 1:25 people carry the mutant gene. It is rare in Asians.

AAT deficiency liver disease is caused by the presence of a mutated AAT protein called Z-AAT. This is due to a mutation in the SERPINA1 gene, which contains the information to produce the AAT protein.

AAT is produced by the liver, and normally released into the bloodstream where it travels to the lungs. In presence of the Z mutation, the conformation of the Z-AAT (i.e. its 3D shape) is modified, and this leads to formation of protein polymers (polymerization is a process that can be compared to putting beads on a necklace for instance). Because the polymers are very large in comparison to the individual protein, they cannot be secreted into the circulation. Instead, they remain in the liver cells, called hepatocytes. There, they slowly accumulate in large amounts in the endoplasmic reticulum of the hepatocytes, in the form of globules (see below).

Clinically, this leads to fibrosis, cirrhosis, and ultimately hepatocellular carcinoma and/or liver failure. There is no treatment currently available. Patients whose liver function is highly affected will be in need of a liver transplant. There is therefore currently an unmet medical need for this severe condition, and several novel therapeutics are being actively investigated. One of the proposed strategies is gene therapy.

Our therapeutic strategy: silencing mutant AAT

We aim to silence the mutant Z-AAT using gene therapy. To achieve this, we have selected a liver-directed delivery of an AAV vector expressing an artificial miRNA targeting all forms of AAT (wild-type and mutant).

We have successfully validated this strategy in preclinical studies. We showed that mice treated with the gene therapy vector present a marked reduction in the level of accumulation of AAT protein (see picture on top of this page).

NEW! The dual-function vector

We have developed a new and proprietary "dual-function vector" for the treatment of alpha-one antitrypsin and we are looking to partner to take it to the clinic.

The dual-function vector is, as its name indicates, a single gene therapy vector that delivers two different therapeutic elements. The first element is responsible for augmentation of normal AAT, the second element drives silencing of mutant AAT. All in one vector!

The idea for this dual-function vector came through our long experience working with the transgenic mouse strain that expresses Z-AAT. The liver of these animals carries a heavy burden, and we realized that doing liver-directed gene augmentation only may be detrimental. Therefore we combined our augmentation and silencing vectors in one, did several rounds of optimization in mice, and now have a potent dual-function vector.

This program is ready to enter its final preclinical phase and be validated in large animals. For this stage we are looking for partners/sponsors. We already have the endorsement and financial support of The Alpha-1 Project, a subsidiary of the Alpha-1 Foundation which funds highly promising drug therapies in the translational research or clinical trial stage of development to speed the commercialization of these therapies.