When an Alpha is asked about how their liver is doing, the answer is almost always related to what their last healthcare professional said. Symptoms occur in Alpha-1 liver disease at a stage late in the course of disease progression, so until your liver disease is relatively advanced, you usually won’t be able to assess how well your liver is functioning without a test at your doctor’s office. But what would happen if a new medication is proven to prevent liver disease progression? And what if that liver medication works best with mild degrees of liver scarring but is not as effective once symptoms become severe? This article will test our collective wisdom since the research study data is not yet final. However, the possibility that an effective liver disease therapy for Alpha-1 will emerge is high. This hope is based on the many liver therapies in the pipeline for alpha-1 antitrypsin deficiency (AATD).

We should remember that the cause of AATD liver disease is the accumulation of misfolded alpha-1 antitrypsin (AAT) and polymers inside the liver cells. Since each of the medications described below works in slightly different ways to decrease the liver disease burden, it is possible that each could be effective and theoretically could be given in combination. This article will describe the mechanisms by which these drugs could work; but, is not designed to pick winners or losers in the race toward a cure. Long-term experience suggests that winners and losers are at best difficult to choose in medicine, and at worst could limit access to a potential cure.

The first medication class that may fix the liver is gene therapy. Because the Z mutation is a single point mutation, all we need to do is to get into the nucleus of 150 trillion cells that make up a normal liver and correct this single gene. Or maybe, if we correct only a small portion of the liver cells and the corrected cells are not as sick as the cells with Z genes, then we could let the corrected cells gradually take over the liver as they divide more efficiently than the previous liver cells. There are multiple ways that gene therapy can be delivered and the details are important. The critical issues that define the strategies for this therapeutic class are differences in liver cell targeting, off-target effects, efficiency of gene correction, and assuring safety.

Old thoughts were that correction of DNA is necessary to get an effect on AAT production. From our high school chemistry days, we all remember that DNA is read by a complementary strand of RNA. The RNA then transcribes the AAT protein inside the cellular organelle called the endoplasmic reticulum. The process of transcription is also subject to manipulation. The science of short-interfering RNAs (siRNA) has been used in other diseases to stop production of an unwanted protein. In the case of Z AATD, stopping production of all the Alpha-1 would let the liver cells heal without needing to handle the large burden of misfolded protein. The consequence is that blood levels of AAT would drop further from their current very low levels, but the liver may be able to heal and decrease the scar that is present. Similarly, attempts to induce correctly coding RNA for MM Alpha-1 are being attempted.

The next strategy that has been used is to improve folding of the misfolded AAT protein. If the folding can be adequately corrected with a pill, then the AAT could get out of the liver cell and into the bloodstream. Since polymer formation is dependent on the amount of misfolded protein, the number of toxic polymers could be reduced and the liver may heal, with or without producing a normal AAT level in the blood. Therefore, the best-case scenario for this class of medications would be a liver that heals from having less misfolded protein and polymers and a blood level that normalizes because the AAT moves out of the liver cells into the blood.

The last area of active research is to target the pathways that degrade misfolded proteins. If these pathways can be sped up, then the misfolded protein-associated toxicity to the cell might be less. There are fewer drugs being applied to this area of research, but understanding the fate of AAT and AAT polymers is important to design these drugs.

It is crucial to the development of these therapies that our Alpha-1 community continues to participate in clinical research trials. These drugs are unique to Alpha-1 and if the community cannot enroll in these studies, then the funding for these studies goes somewhere else. To stay up-to-date on the latest Alpha-1 trial announcements and studies, join the Alpha-1 Foundation’s Alpha-1 Research Registry.

Please consider helping these drugs toward the market; the life you save may be your own.