The promise and challenges of bioengineered recombinant clotting factors.
The past 10 years of clinical experience have demonstrated the safety and efficacy of recombinant clotting factors. With the adoption of prophylactic strategies, there has been considerable progress in avoiding the complications of hemophilia. Now, insights from our understanding of clotting factor structure and function, mechanisms of hemophilia and inhibitors, gene therapy advances and a worldwide demand for clotting factor concentrates leave us on the brink of embracing targeted bioengineering strategies to further improve hemophilia therapeutics. The ability to bioengineer recombinant clotting factors with improved function holds promise to overcome some of the limitations in current treatment, the high costs of therapy and increase availability to a broader world hemophilia population. Most research has been directed at overcoming the inherent limitations of rFVIII expression and the inhibitor response. This includes techniques to improve rFVIII biosynthesis and secretion, functional activity, half-life and antigenicity/immunogenicity. Some of these proteins have already reached commercialization and have been utilized in gene therapy strategies, while others are being evaluated in pre-clinical studies. These novel proteins partnered with advances in gene transfer vector design and delivery may ultimately achieve persistent expression of FVIII leading to an effective long-term treatment strategy for hemophilia A. In addition, these novel FVIII proteins could be partnered with new advances in alternative recombinant protein production in transgenic animals yielding an affordable, more abundant supply of rFVIII. Novel rFIX proteins are being considered for gene therapy strategies whereas novel rVIIa proteins are being evaluated to improve the potency and extend their plasma half-life. This review will summarize the status of current recombinant clotting factors and the development and challenges of recombinant clotting factors bioengineered for improved function.
Pipe
S W
SW
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA. ummdswp@med.umich.edu
D000818:Animals; D030801:Animals, Genetically Modified; D001779:Blood Coagulation Factors / Q000737:chemistry* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005164:Factor IX / Q000627:therapeutic use*; D005169:Factor VIII / Q000627:therapeutic use*; D015942:Factor VIIa / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods; D006467:Hemophilia A / Q000188:drug therapy* / Q000628:therapy*; D006801:Humans; D015202:Protein Engineering / Q000379:methods*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000627:therapeutic use*
D001779:Blood Coagulation Factors; D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII; D005164:Factor IX; D015942:Factor VIIa