Hemophilia: New Protein Therapeutics

Abstract

Therapeutic advances for patients with hemophilia have resulted in reduced mortality, improved joint outcomes, safety from blood-transmitted pathogens, improved quality of life, and a normalized life span in the developed world. The production of recombinant coagulation factors has increased the worldwide capacity for replacement therapy and facilitated aggressive prophylactic therapy. However, this has come at significant cost, and barriers remain to broad application of prophylaxis. Recombinant DNA technology remains a promising platform to develop novel hemophilia therapeutics with improved functional properties to try to overcome some of these remaining barriers. Bioengineering strategies have produced novel therapeutics with increased production efficiency, increased potency and resistance to inactivation, prolonged plasma half-lives, and reduced immunogenicity. Alternative nonbiologic therapies may lead to new treatment paradigms. The current pipeline of new technologies and products is promising and growing with several agents already advancing from preclinical to clinical trials.

Postępy w leczeniu chorych na hemofilie

“…Sklonowanie genu czynnika krzepnięcia IX (FIX, factor IX) w 1982 roku i genu czynnika krzepnięcia VIII (FVIII, factor VIII) w 1984 roku umożliwiło opracowanie technologii produkcji rekombinowanych czynników krzepnięcia, których istotną przewagą nad osoczopochodnymi czynnikami krzepnięcia jest niższe ryzyko przeniesienia cząstek zakaźnych [1,2]. Ale przewaga leków rekombinowanych nie ogranicza się do większego bezpieczeństwa ich stosowania.…”

Present and Future of Pediatric Hemophilia Treatment

“…Finally, missense mutations leading to premature stop codons in FVIII or FIX occur in approximately 10% to 15% of persons with hemophilia A or B, respectively. Small molecules have been developed that can facilitate translational read through of premature stop codons [7,12]. In conclusion we can say that the research and innovation strategies are moving forward so that we can ensure an optimal quality of life.…”

“…Purified plasmaderived factor VIII (pdFVIII) concentrates have been available since the 1970s, but require rigorous plasma donor screening and viral inactivation technologies to reduce the risk for blood-transmitted pathogens. Recombinant FVIII (rFVIII) concentrate has proven to be a remarkable facsimile to pdFVIII with regard to biochemical and hemostatic properties, and has a similar pharmacokinetic profile with a half-life of roughly 12 hours [7]. After almost 20 years of experience with rFVIII, there are clearly opportunities to extend recombinant DNA technology to further enhance replacement therapy.…”

“…Furthermore, PSA, unlike PEG, are naturally occurring and biodegradable, which offers a potential advantage when administering large doses of a biologic therapy over a prolonged period of time. PSA modification is now being explored through direct conjugation of rFVIII, FIX, FVIIa, and vWF [7]. Formulation with PEGylated liposomes is an established process that has been used to extend the half-life of a broad range of therapeutic proteins, including FVIII.…”

Hemophilia A. Considerations in the dental management of pediatric patients. A case report.

“…The amount of factor VIII concentrate needed depends on bleeding severity, the site and patient's body built [12][13][14] . Figure 1.…”