Haemophilia prophylaxis in young patients–a long‐term follow‐up

Löfqvist, Thomas; Nilsson, Inga Marie; Berntorp, Erik; Pettersson, Holger

doi:10.1046/j.1365-2796.1997.130135000.x

Cited by 322 publications

(342 citation statements)

References 8 publications

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“…Prophylactic regimens significantly reduce arthropathy and soft tissue bleeding in patients with severe hemophilia who are begun on prophylaxis at 1 to 2 years of age and whose trough levels of FIX are maintained above 1%. 1,5,6,28 In contrast to patient studies, we found that despite plasma cFIX levels of 1-2%, bleeding still occurred in both dogs. The majority of the bleeding episodes were trauma-related but spontaneous bleeding did occur.…”

Section: Discussioncontrasting

confidence: 99%

“…4 Bolus infusion with FIX concentrate provides circulating FIX with a half-life of 18-30 h. Effective prophylactic treatment can be achieved by twice-a-week infusions when trough levels are at least Ͼ1% FIX. 5 Such prophylactic regimens are the standard of care for hemophilic children in Sweden and several European countries. 5,6 However, due to higher factor requirement, the cost of prophylactic treatment is prohibitive for most adult patients.…”

Section: Introductionmentioning

confidence: 99%

“…5 Such prophylactic regimens are the standard of care for hemophilic children in Sweden and several European countries. 5,6 However, due to higher factor requirement, the cost of prophylactic treatment is prohibitive for most adult patients.…”

Section: Introductionmentioning

confidence: 99%

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Persistent expression of canine factor IX in hemophilia B canines

Chao¹,

Samulski²,

Bellinger

et al. 1999

Gene Ther

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We previously demonstrated that direct intramuscular required plasma infusion for spontaneous and traumatic injection of recombinant adeno-associated virus (rAAV) bleeding events. Inhibitors to cFIX protein were not carrying the human FIX (hFIX) cDNA can safely be admindetected in either animal by Bethesda assay. Neutralizing istered to hemophilic B canines and express human factor antibodies directed against AAV-2 capsid were pro-IX protein; however, the functional activity of the hFIX pronounced and persistent. Vector DNA and mRNA trantein could not be assessed due to anti-human FIX antibody scripts were detected only at the injected skeletal muscle (inhibitor) formation. To test the therapeutic efficacy of tissue. Analysis of both high and low molecular weight DNA rAAV in hemophilic dogs, rAAV type 2 (rAAV2) carrying identified both replicative episomal and integrated AAV canine FIX (cFIX) cDNA was injected into the skeletal musspecies. These results demonstrate that persistent cle of two dogs at doses of 10 12-13 particles. Circulating secretion of the FIX transgene protein, necessary for succFIX protein levels were maintained for 1 year at levels of cessful gene therapy of hemophilia B, can be achieved 1-2% of normal. Hemostatic correction (WBCT and APTT) using the parvovirus-based rAAV vector. paralleled plasma FIX antigen levels. Both dogs still

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Persistent expression of canine factor IX in hemophilia B canines

Chao¹,

Samulski²,

Bellinger

et al. 1999

Gene Ther

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“…7 Prophylaxis, the routine scheduled replacement of factor VIII, is standard care for patients who have severe hemophilia A without inhibitors, because of its ability to prevent bleeding. [8][9][10][11][12] However, for patients with inhibitors who have refractory bleeding with serious consequences and who could derive an even greater benefit from prevention of bleeding, factor VIII prophylaxis is ineffective.…”

Section: Discussionmentioning

confidence: 99%

Anti-Inhibitor Coagulant Complex Prophylaxis in Hemophilia with Inhibitors

et al. 2011

Self Cite

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“…The continuous presence in the bloodstream of amounts of F.IX as low as 1% of normal has been shown to be clinically relevant in terms of preventing or substantially reducing the frequency of spontaneous bleeds into the joints, soft tissues, or intracranial space. 9,10 Factor IX is normally synthesized in the liver, but from a gene therapy standpoint, there is a strong motivation for evaluating alternative target tissues in this population because of the high prevalence of viral hepatitis (approximately 90%) among adults with severe hemophilia. [11][12][13] Skeletal muscle has been extensively tested as a target tissue for gene delivery.…”

Section: Introductionmentioning

confidence: 99%

Posttranslational modifications of recombinant myotube-synthesized human factor IX

Arruda

Hagstrom

Deitch

et al. 2001

Blood

116

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Recent data demonstrate that the introduction into skeletal muscle of an adenoassociated viral (AAV) vector expressing blood coagulation factor IX (F.IX) can result in long-term expression of the transgene product and amelioration of the bleeding diathesis in animals with hemophilia B. These data suggest that biologically active F.IX can be synthesized in skeletal muscle. Factor IX undergoes extensive posttranslational modifications in the liver, the normal site of synthesis. In addition to affecting specific activity, these posttranslational modifications can also affect recovery, half-life in the circulation, and the immunogenicity of the protein. Before initiating a human trial of an AAV-mediated, muscle-directed approach for treating hemophilia B, a detailed biochemical analysis of F.IX synthesized in skeletal muscle was carried out. As a model system, human myotubes transduced with an AAV vector expressing F.IX was used. F.IX was purified from conditioned medium using a novel strategy designed to purify material representative of all species of rF.IX in the medium. Purified F.IX was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), N-terminal sequence analysis, chemical ␥-carboxyglutamyl analysis, carbohydrate analysis, assays for tyrosine sulfation, and serine phosphorylation, and for specific activity.Results show that myotube-synthesized F.IX has specific activity similar to that of liver-synthesized F.IX. Posttranslational modifications critical for specific activity, including removal of the signal sequence and propeptide, and ␥-carboxylation of the N-terminal glutamic acid residues, are also similar, but carbohydrate analysis and assessment of tyrosine sulfation and serine phosphorylation disclose differences. In vivo experiments in mice showed that these differences affect recovery but not half-life of muscle-synthesized F.IX. (Blood. 2001;97:130-138)

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Haemophilia prophylaxis in young patients–a long‐term follow‐up

Cited by 322 publications

References 8 publications

Persistent expression of canine factor IX in hemophilia B canines

Persistent expression of canine factor IX in hemophilia B canines

Anti-Inhibitor Coagulant Complex Prophylaxis in Hemophilia with Inhibitors

Posttranslational modifications of recombinant myotube-synthesized human factor IX

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