Method determines plausible forms of ancestral blood clotting protein

Ancestral sequence reconstruction (ASR) is a computational method in which the sequences of closely related proteins from different species are used to infer ancient protein sequences within a predicted evolutionary tree. Christopher B. Doering of Emory University, Eric A. Gaucher of Georgia Tech, and coworkers have used ASR to improve the pharmaceutical properties of coagulation factor VIII, a protein essential to blood clotting (Nat. Biotechnol. 2016, DOI: 10.1038/nbt.3677). Deficiency in factor VIII is the cause of hemophilia A, and infusion of the protein is used to treat the disease. Unfortunately, many people who receive therapeutic factor VIII develop antibodies to it. Plus, recombinant human factor VIII is hard to produce in cell culture manufacturing systems. By using ASR, Doering and coworkers constructed a family tree of factor VIII ancestors from which they selected 14 proteins for evaluation. Several of these ancestral proteins were produced more efficiently, were more potent, were less immune-reactive, and remained active longer than modern human factor VIII. Doering’s group is now working with the ancestral sequences as potential gene therapy agents, as well as extending the general ASR approach to other pharmaceutically relevant blood coagulation factors.