branched PEGs and random vs site-specific attachments to clottin

branched PEGs and random vs. site-specific attachments to clotting proteins have been investigated. The most advanced of these approaches is site-specific chemical modification

of FVIII. To begin with, a large number of surface-exposed cysteine substitutions were introduced into FVIII and the specific activities of the novel proteins determined. On the basis of these initial studies, several of the cysteine-substituted molecules were then conjugated through PEG-maleimide attachments [13]. Screening of variant expression level, PEGylation yield, and functional assay identified several conjugates retaining full in vitro coagulation activity and VWF binding. Subsequent studies in haemophilic mice demonstrated a significantly extended half-life with di-PEGylated FVIII molecules and excellent in vivo efficacy compared with traditional BDD-FVIII (Fig. 2) [14]. A study in Kinase Inhibitor Library cost humans is currently ongoing. Site-directed glycoPEGylation appears to have an even greater place in terms of improving the pharmacokinetic properties of rFIX. In the first human dose trial conducted in 16 PTPs with haemophilia B [15], the half-life of N9-GP at the same dose level as their previous product was five times longer (93 h vs. 18 h), which represents a substantial difference and suggests that such a formulation of FIX could be administered at intervals of once

weekly or even longer. As always, it will be interesting to see what happens once the product reaches clinical practice and its use becomes more Liproxstatin-1 mouse widespread. Another promising approach to prolong the half-life of rFVIII and rFIX concentrates involves the generation of fusion proteins (through genetic fusion constructs) with either albumin or immunoglobulin. To date, studies using a FIX-monomeric Fc immunoglobulin fusion in a variety of animal almost models have shown that the modified FIX proteins experience a 3-

to 4-fold extension of half-life along with excellent haemostatic efficacy [13]. Despite these somewhat remarkable results in terms of strategies underway to prolong the half-life of recombinant factor concentrates, a number of unresolved questions remain.  Will prolongation of FVIII half-life prove to be as attainable as that for FIX? In closing, it is important to emphasize once again that patients with haemophilia and related diseases (VWD) currently enjoy effective and safe treatment and have a quasi normal life-expectancy. As such, any attempt of a cure (e.g. gene transfer) must be achieved at no risk to the patient. There are a number of unresolved issues with haemophilia treatment, not the least of which is the lack of availability of factor concentrates to two-thirds of the world’s population with the condition. Although the World Federation of Haemophilia is trying to tackle this issue, with great courage and with some results, it remains a formidable task.

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