Proposing Complement C3 RNAi for Treating COVID19

Whereas my last blog considered lung-targeted RNAi for addressing COVID19, this entry will look at what a liver-directed RNAi approach could do for the disease.  It is in the liver that RNAi Therapeutics have proven to be extremely potent.  Moreover, it is amenable to subcutaneous administration and therefore appropriate for the current pandemic.

It has quickly become apparent that in a subgroup of patients COVID19 is associated with liver complications.  Managing these with gene silencing of resident liver proteins may be possible in theory and could be contemplated.  More interesting, however, would be intervening upstream of the liver in the respiratory tract.  

It is reported that it is an overactive (innate) immune system rather than cellular damage (cytopathic) by the virus itself that can cause the virus to be fatal.

And when it comes to an immune approach with RNAi at the moment, the complement pathway, many components of which are predominantly expressed by the liver and secreted into circulation comes to mind.

Interestingly, a relatively recent paper (Gralinski et al, 2018) in a mouse model of SARS-CoV-2-related SARS has shown that genetic complement C3 knockout lessened lung damage and overall health as measured by body weight.  This was associated with a reduced influx of neutrophils which are the carpet-bombers of the immune system.

The next question to be asked is that since RNAi gene silencing is not instantaneous but takes time to manifest, whether such intervention would be timely enough in a given patient.  For this, my assessment is that it should be possible based on the pharmacodynamics of a C3 RNAi in development by Silence Therapeutics (SLN500) and Mallinckrodt IF the disease can be diagnosed in time.

Accordingly, it took about 4 days for robust C3 silencing in mice which compares to the about 7-10 days it takes for SARS-CoV-2 to move from the upper respiratory tract (as manifested e.g. by throat pain) to the lower lungs where the critical battleground is.

These are extraordinary times and I believe this approach should be considered.  Besides Silence Therapeutics and Mallinckrodt, Alnylam, and Dicerna (in partnership with Alexion) are also working on RNAi for the complement system.  A monoclonal antibody approach may also be envisioned and could have advantage of a faster onset of action, but may lag in development timelines.