Acute vs Chronic: Pondering siRNA liver indications

by Robert Kruse

The field of siRNA therapeutics has been slow in development after its original discovering by Fire and Mello in 1998, but has made recent significant progress. Various siRNA companies have mostly focused on chronic diseases and indications, seeking to use siRNA as a weekly (or monthly) treatment much like current drugs. siRNA therapies could target cholesterol levels, HBV, cancer, or transthyretin all of which would need to be continuously dose over months of time or longer.

Given the potentially high cost of scaling siRNA manufacturing, as well the need for intravenous routes for some formulations, it is suggested that alternative indications may be useful, where the power of siRNA knockdown could be leveraged against current undruggable targets. In particular, siRNA delivery to the liver seems to have reached optimized levels that are efficient enough for human therapies. This should be considered a relatively safe bet for companies and investors. Focusing on the liver then, acute fulminant hepatitis (acute liver failure) is an important disease treated at the intensive care units of hospitals around the world. It can be caused by drugs and viruses among other ailments. The disease can be fatal if not properly treated, and even with proper treatment, may result in the need for liver transplant.

While an acute disease, there is a significant potential value being added in preventing extremely expensive downstream therapies. In the past, the death rate approached 80% before the advent of newer strategies of supportive care. Still, a significant portion of patients die from acute liver failure. Many others depend on liver transplant for survival, which isn't available for many patients with surgery carrying its own risks. It is suggested here that this represents an excellent indication for siRNA then, where only 2 or 3 doses over 1 week could save a person's life. One caveat could be the potential toxicity of the delivery vector in the background of fulminant hepatitis, so this should be considered when companies develop strategies to treat liver failure. Another caveat is the kinetics of siRNA knockdown, which could take days, or more, for significant knockdown. Thus, siRNA would need to be administered to patients before symptoms become progressively worse, and thus might not be applicable for clinical scenarios where a patient's liver is unrecoverable within a single day, in which case, liver transplant would remain the gold standard.

In screening the literature for work done previously for acute hepatic indications, I found a Nature Medicine paper from 2003 where they knocked down the Fas protein with siRNA in order to prevent fulminant hepatitis. Fas is the key mediator of hepatic apoptotic signaling, as mediated through immune cells expressing Fas ligand. T cells and Kupffer cells (liver macrophages). This strategy was very successful in preventing liver failure induced by concavalin A activation of immune cells, or with an agonistic Fas antibody, and should be broadly applicable to any mechanisms where immune infiltration is the cause of acute liver failure, such as acute viral hepatitis.

While useful for preventing immune reaction mediated acute liver failure, other indications such as acetaminophen toxicity or alcohol poisoning would likely need other targets in order to stabilize hepatocytes from liver death. One example might be targeting the Bax protein, which promotes apoptosis via the intrinsic apoptosis pathway, promoting cytochrome c release. Careful examination of various hepatic mRNA's during liver failure could identify more targets that might be useful in preserving hepatocytes. Furthermore, while the discussion here focuses on hyperacute presentations, there are acute and subacute presentations of hepatic failure that could present over several weeks, if the goal of biotech companies would be to increase doses for more profit.

While I haven't done an exhaustive search of all siRNA company's portfolios, I don't think a line of programs for acute liver failure has been openly disclosed by them. Given the limited ability of small molecules to currently rescue hepatocytes from death, it appears that this might be a relatively safe indication where hepatocytes could be efficiently targeted and modulated by siRNAs in unique ways. I would recommend scientists at Arrowhead, Alnylam, and others to consider this possibility going forward, given its important medical need.