ALN-CC5
Excessive complement activation is related to the pathogenesis of various diseases, and targeted inhibition of the complement protein during the occurrence of these diseases may have a good effect on the treatment of diseases. Complement C5 is a potential target for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome and myasthenia gravis (MG). ALN-CC5 is a small interfering RNA (siRNA) that can inhibit C5 activity in humans, primates and rodents. It can silence the C5 gene and has shown good therapeutic effects on the above diseases in the current trials.
Figure 1. C5 Silencing reduces proteinuria and glomerular MAC deposition. (Boeodovsky, 2014)
The Therapeutic Mechanism of ALN-CC5
The liver produces essentially the entirety of C5 and other complement pathway proteins. RNAi is a natural cellular mechanism that regulates gene expression. Synthetic small interfering RNA can be designed to target endogenous mRNA transcripts of any gene. By combining N-acetylgalactosamine (GalNAc) with asialoglycoprotein receptor (ASGPR), siRNA targeting liver-expressed genes (such as C5) can be efficiently and specifically delivered to hepatocytes for hepatocyte expression gene-specific silencing. The GalNAc-siRNA conjugate injected subcutaneously (SC) has proven to be specific for multiple target genes in animals, and can achieve stable and long-lasting inhibition. Also, several investigational RNAi therapeutics have been evaluated in human clinical trials, demonstrating favorable safety results and positive efficacy, with the potential for monthly or less frequent subcutaneous dosing.
Animal Experiments Related to ALN-CC5
To further promote the development of ALN-CC5 as an RNAi therapeutic agent, the scientists conducted a drug efficacy test using rodents and primates as models, and examined the C5 silencing and complement activity inhibition after administration. The experimental results show that the multi-dose SC ALN-CC5 treatment can lead to the continuous reduction of C5 in crab serum, and the residual amount of residual protein ≤3%. C5 reduction was associated with >90% and >95% inhibition of classical and alternative complement pathways, respectively, as measured by ELISA-based assays. In different dosing regimens, the time when the inhibitory effect of ALN-CC5 reached the maximum extent was consistent, indicating that the decrease in C5 content was mainly limited by the half-life of the protein.
As of now, ALN-CC5 has shown good safety and tolerability in toxicology studies in rats and non-human primates. In addition to wild animals, ALN-CC5 has also been tested in various disease models related to complement activation. In the anti-collagen antibody-induced arthritis (CAIA) model, murine C5 silencing is very effective, and its disease-modifying activity is the same as anti-C5 antibody. In the rat model of membranous nephropathy, C5 silencing can effectively reduce proteinuria. It was observed in both models that the upregulation of C5 expression did not affect the degree of C5 silencing, suggesting that ALN-CC5 may be effective in the case of inflammation. These data demonstrate that circulating liver-derived C5 plays an important role in mediating the pathology of the extrahepatic site and the potential use of RNAi therapeutics targeting C5.
Overall, ALN-CC5, as an RNAi therapeutic agent targeting C5, has obvious gene suppression ability and has demonstrated the potential of treating complement-mediated diseases in current animal experiments. Its advantages in safety and administration methods also make ALN-CC5 highly motivated to continue development.
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Reference
- Boeodovsky, A.; et al. (2014). Aln-CC5, an investigational RNAi therapeutic targeting C5 for complement inhibition. Complement. 20: 40.
