A Key Revelation

Although the membrane attack complex (MAC) may have played an important evolutionary role, in today’s world it may be largely unnecessary. This has been revealed through blood donation services in Japan and Korea, where it has been found that one Japanese in 1,000 and one Korean in 1,400 have a mutation in the C9 gene, which results in a truncated and incompetent C9 protein[1]–[7]. This mutation prevents these individuals from making a functional MAC. The statistics mean that there are more than 150,000 Japanese and 36,000 South Koreans who are unable to generate the MAC.

Interestingly, there is little known about these C9-deficient individuals because they do not come to the attention of physicians or hospitals and appear to lead healthy lives. While there have been reports of elevated risk of Neisseria infection in individuals with terminal complement cascade protein deficiencies, it does not seem to be a significant problem for these C9-deficient individuals who appear to generally enjoy good health[8].  Given the basic science, these individuals should be preferentially spared from complement-mediated autoimmune and degenerative disorders.  This population-level evidence suggests that selective inhibition of MAC formation by blocking C9 with a suitable pharmaceutical agent should be a viable therapeutic strategy on both a short and long term basis.

Complement Protein C9

Aurin Biotech’s drug candidates bind to C9 thus blocking its activity.  This leads to the temporary biochemical equivalent of being born with what could be viewed as a fortunate genetic adaptation.

Illustration of the membrane attack complex (MAC) showing sequential assembly of C5b, C6, C7, C8 and multiple copies of C9. Source: Aleshin et al. JBC 287 p10210.

Illustration of the membrane attack complex (MAC) showing sequential assembly of C5b, C6, C7, C8 and multiple copies of C9.
Source: Aleshin et al. JBC 287 p10210.


References & Further Reading

[1]      T. Horiuchi, H. Nishizaka, T. Kojima, T. Sawabe, Y. Niho, P. M. Schneider, S. Inaba, K. Sakai, K. Hayashi, C. Hashimura, and Y. Fukumori, “A non-sense mutation at Arg95 is predominant in complement 9 deficiency in Japanese.,” J. Immunol., vol. 160, no. 3, pp. 1509–13, Feb. 1998.

[2]      H. J. Kang, H. S. Kim, Y. K. Lee, and H. C. Cho, “High incidence of complement C9 deficiency in Koreans.,” Ann. Clin. Lab. Sci., vol. 35, no. 2, pp. 144–8, Jan. 2005.

[3]      V. Khajoee, K. Ihara, R. Kira, M. Takemoto, H. Torisu, Y. Sakai, J. Guanjun, P. M. Hee, K. Tokunaga, and T. Hara, “Founder effect of the C9 R95X mutation in Orientals.,” Hum. Genet., vol. 112, no. 3, pp. 244–8, Mar. 2003.

[4]      R. Kira, K. Ihara, H. Takada, K. Gondo, and T. Hara, “Nonsense mutation in exon 4 of human complement C9 gene is the major cause of Japanese complement C9 deficiency.,” Hum. Genet., vol. 102, no. 6, pp. 605–10, Jun. 1998.

[5]      R. Kira, K. Ihara, K. Watanabe, S. Kanemitsu, S. U. Ahmed, K. Gondo, K. Takeshita, and T. Hara, “Molecular epidemiology of C9 deficiency heterozygotes with an Arg95Stop mutation of the C9 gene in Japan.,” J. Hum. Genet., vol. 44, no. 2, pp. 109–11, Jan. 1999.

[6]      R. Tsujimura, H. Nishimukai, T. Okiura, Y. Fukumori, R. Tanabe, C. Orimoto, and N. Ueda, “Typing of the nt343C>T (R95X) allele of the C9 gene by PCR-SSP and the allele frequency of R95X in five ethnic populations.,” Leg. Med. (Tokyo)., vol. 11 Suppl 1, pp. S482–3, Apr. 2009.

[7]      K. Witzel-Schlömp, P. J. Späth, M. J. Hobart, B. A. Fernie, C. Rittner, T. Kaufmann, and P. M. Schneider, “The human complement C9 gene: identification of two mutations causing deficiency and revision of the gene structure.,” J. Immunol., vol. 158, no. 10, pp. 5043–9, May 1997.

[8]      M. Lee, J. P. Guo, E. G. McGeer, and P. L. McGeer, “Aurin tricarboxylic acid self-protects by inhibiting aberrant complement activation at the C3 convertase and C9 binding stages,” Neurobiol. Aging, vol. 34, no. 5, pp. 1451–1461, May 2013.