期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 19, 期 11, 页码 2744-2750出版社
WILEY
DOI: 10.1111/jth.15497
关键词
Factor VIII; Hemophilia A; immunotherapy; lysophosphatidylserines; nanoparticles; neutralizing antibodies
资金
- National Institutes of Health [R01 HL-70227]
The study demonstrates that using FVIII associated with Lyso-PS nanoparticles significantly reduces inhibitor development and improves the plasma survival of FVIII following intravenous administration. Additionally, reduction in inhibitor formation can also be achieved using Lyso-PS nanoparticles through the user-friendly oral route of administration.
Background The development of antidrug antibodies, also termed inhibitors, against administered factor VIII (FVIII) is one of the major complications in the clinical management of hemophilia A. Once formed, these inhibitory antibodies abrogate the activity of FVIII, resulting in loss of hemostatic efficacy and patients are subjected to increased risk of bleeding tendencies. Current treatment options after inhibitor development are expensive and ineffective in some cases. Therefore, treatment strategies that can prevent inhibitor formation is an effective approach in the management of hemophilia A. Objectives We aimed to evaluate and discuss the use of a tolerogenic form of FVIII as an immunotherapy strategy to prevent inhibitor risk. Methods FVIII was associated with nanoparticles containing lysophosphatidylserine (Lyso-PS) and administered to hemophilia A mice via intravenous route. These animals then received weekly rechallenge injections with free FVIII, and plasma was collected at the end of the study to evaluate for inhibitor development. To investigate whether Lyso-PS nanoparticles influence the plasma survival of FVIII, a pharmacokinetic study following a single intravenous administration of FVIII in the presence and absence of Lyso-PS nanoparticles was performed. For dosing convenience, the tolerogenic effect of Lyso-PS nanoparticles following oral administration was also examined. Results and conclusions The results demonstrated that FVIII associated with Lyso-PS nanoparticles significantly reduced inhibitor development while improving plasma survival of FVIII following intravenous administration, suggesting a multifunctional FVIII form to improve clinical utility. Additionally, reduction in inhibitor formation can also be achieved using Lyso-PS nanoparticles through the user-friendly oral route of administration.
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