Site-Specific Pegylation of Rfviii Results in Prolonged in Vivo Efficacy

Murphy, John E.; Pan, Chun; Barnett, Thomas; Mei, Baisong; Strauss, Jonathan B.; Tjandra, Hendri; Tang, Li; Esmon, Pamela C.; Newgren, James O.; Landskroner, Kyle; Parmathi, M.; Severs, Joanne C.; Teare, John; Jiang, Hong; Devens, Bruce H.; Pierce, Glenn F.; Konstantinov, Konstantin N.; Fournel, Michael A.

doi:10.1111/j.1538-7836.2007.tb01780.x

Cited by 3 publications

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“…Advances may also materialize through DNA technology that may be able to modify coagulation factor molecules and render them more active and/or less antigenic [60]. Several approaches have been attempted in the laboratories, but at the moment those that are undergoing clinical trials are based upon the PEGylation of factors, or of factor vehicles such as liposomes [54][55][56][57][58][59].…”

Section: What Next: Building On Strengthmentioning

confidence: 99%

“…This would be a significant step forward, considering that in countries that can afford primary prophylaxis, the main obstacles to its widespread adoption are the difficulties of venous access. Several pharmaceutical companies are currently developing factors with longer half-life, which would require less frequent venipunctures [54][55][56][57][58][59]. Advances may also materialize through DNA technology that may be able to modify coagulation factor molecules and render them more active and/or less antigenic [60].…”

Section: What Next: Building On Strengthmentioning

confidence: 99%

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Back to the future: a recent history of haemophilia treatment

2008

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Summary. In the last few decades, the management of patients with haemophilia has witnessed dramatic improvements, through the larger availability of safe plasma-derived and recombinant products for replacement therapy. Another important step forward is the progressively larger-scale implementation of primary prophylaxis in children. Currently, the main problem in patients with haemophilia is the onset of antibodies inactivating the infused clotting factor (inhibitors), even though immune tolerance regimens that are able to eradicate inhibitors and the availability of products that bypass the intrinsic coagulation defects have dramatically improved the management of these patients. Cure of haemophilia through gene transfer is being attempted, but relatively, it is far from being implemented on a large scale. It is likely that further improvements in replacement therapy will occur in the near future, through the availability of new-therapeutic tools such as factors VIII and IX with longer half-lives, more potent bypassing agents and factors extracted from the milk of transgenic animals.

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Section: What Next: Building On Strengthmentioning

confidence: 99%

Section: What Next: Building On Strengthmentioning

confidence: 99%

Back to the future: a recent history of haemophilia treatment

2008

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“…28 These included mutagenesis of the FVIII molecule to increase its stability [29][30][31] and direct PEGylation of the FVIII protein. [32][33][34][35] Modifying a large and complex protein such as FVIII is a difficult undertaking, though. The integrity of multiple active sites must be maintained and protein conformation must be preserved.…”

Section: Bypassing Agentsmentioning

confidence: 99%

The use of PEGylated liposomes in the development of drug delivery applications for the treatment of hemophilia

Yatuv

Robinson²,

Dayan-Tarshish³

et al. 2010

IJN

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Hemophilia A is a rare X-linked bleeding disorder caused by lack or dysfunction of coagulation factor VIII (FVIII). Hemophilia A is treated with replacement therapy, but frequent injections of the missing FVIII often lead to the formation of inhibitory antibodies. Patients who develop high levels of inhibitors must be treated with bypassing agents such as activated FVII (FVIIa). Both FVIII and FVIIa have short half-lives and require multiple injections. Long-acting forms of these proteins would therefore reduce the frequency of injections, improve patient compliance and reduce complications. In this article we present a new platform technology that produces long-acting forms of FVIII and FVIIa and improves the efficacy of hemophilia treatment. This technology is based on the binding of proteins/peptides to the outer surface of PEGylated liposomes (PEGLip). Binding is dependent on an amino acid consensus sequence within the proteins and is highly specific. At the same time, binding is non-covalent and does not require any modification of the therapeutic agent or its production process. Association of proteins with PEGLip results in substantial enhancements in their pharmacodynamic properties following administration. These improvements seem to arise from the association of formulated proteins with platelets prior to induction of coagulation.

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