High-activity blood coagulation factor VIII or VIII polypeptide variant Gly710Thr

Abstract

The invention relates to a polypeptide variant Gly710Thr of a blood coagulation factor VIII or VIII a with high activity. The mutant does not destroy or inhibit the coagulation activity of FVIII, the coagulation specific activity is 1.6-2 times that of a wild type, and the mutant is more excellent in stability; the mutant obviously improves the drug efficacy of the FVIII, and has a good clinical application prospect.

Description

technical field [0001] The invention belongs to the field of hemophilia, and particularly relates to a highly active coagulation factor VIII or VIIIa polypeptide variant Gly710Thr. Background technique [0002] Lifelong replacement therapy for FVIII is currently the only clinically effective treatment. Since the content of FVIII in plasma is extremely low (100-200ng / ml), the source of concentrated human FVIII is limited, and there is a potential risk of virus transmission. With the development of biotechnology, gene recombinant FVIII gradually replaced plasma-derived FVIII, becoming The agent of choice for replacement therapy. FVIII replacement therapy has greatly improved the condition and quality of life of patients with hemophilia. [0003] Over time, the shortcomings of replacement therapy have become increasingly apparent: First, the production of induced inhibitors is considered to be the most serious complication of replacement therapy, and about 20% to 30% of hemop...

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Problems solved by technology

[0003] As time goes by, the disadvantages of substitution therapy are inevitably exposed more and more significantly: first, the generation of induced inhibitors is considered to be the most serious complication of substitution therapy, and about 20% to 30% of hemophilia A patients will During the course of treatment, FⅧ inhibitors are produced, resulting in reduced curative effect or even failure of replacement therapy; secondly, the half-life of FⅧ is short and the frequency of medication is frequent: the half-life of FⅧ in vivo is only less than 12 hours, in order to maintain its effective plasma concentration and achieve the purpose of preventing bleeding , needs to inject FⅧ3 times a week; again, the cost of FⅧ replacement therapy is expensive, and the average annual replacement therapy cost for patients with severe hemophilia A reaches 100,000 US dollars. It is also increasing year by year, but the cost of expensive medicines still brings a heavy economic burden to families and society

The heavy economic burden is the main reason why most patients with severe hemophilia A in my country are unable to adhere to long-term preventive treatment.

The gene therapy of HA is expected to solve the above problems, freeing patients from the risk of life-long replacement therapy and inhibitors, and has made good progress in recent years, but the expression of FⅧ has been observed to decrease over time in patients receiving this treatment , and some patients still need to cooperate with replacement therapy to maintain the level of FⅧ in the body. The success of gene therapy must first solve the problem of how to maintain the stable expression of blood coagulation factor genes introduced into the body. Although non-replacement therapy may be delayed or at least reduced in the future Exposure to exogenous FⅧ, but replacement therapy will still be the mainstream of HA treatment

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