Delays in maturation among adolescents with hemophilia and a history of inhibitors

Donfield, Sharyne; Lynn, Henry; Lail, Alice; Hoots, W. Keith; Berntorp, Erik; Gomperts, Edward D.

doi:10.1182/blood-2007-05-088062

Cited by 14 publications

(16 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These studies included patients with HIV and HCV infections and varying degrees of haemophilic arthropathy. In addition, the Hemophilia Growth and Development study indicated that bone age among a large number of adolescents with haemophilia was significantly delayed in patients with inhibitors relative to their normal siblings, even among those who were HIV negative . Taken together, these clinical data suggest a primary link between coagulation and bone mineralization as well as demonstrating a significant long‐term health risk in the haemophilia population.…”

Section: Introductionmentioning

confidence: 93%

The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption

et al. 2013

View full text Add to dashboard Cite

Osteopenia and osteoporosis have increasingly become a recognized morbidity of factor VIII (FVIII) deficiency. Recently, we demonstrated that FVIII knockout (KO) mice had significantly decreased bone mass and bone strength despite the fact that they did not have haemarthroses. The aim of this study was to explore the mechanism of bone disease associated with FVIII deficiency. We compared biochemical markers of bone formation and osteoclastogenesis, inflammatory cytokines, as well as static and dynamic histomorphometry of genetically engineered FVIII KO male mice to those of wild-type (WT) controls. At 20 weeks of age, FVIII KO mice, as well as WT controls, were sacrificed. Serum and bones were obtained at the time of sacrifice to study biochemical markers of bone formation (osteocalcin) and osteoclastogenesis (receptor activator of nuclear factor kappa-β and osteoprotegerin), levels of inflammatory cytokines (interleukin-1α and interferon-β) and to perform static and dynamic histomorphometry of tibia cancellous bone. There was no difference in the biochemical markers of bone formation or osteoclastogenesis. However, there were differences in the two bone-associated cytokines studied. In addition, histomorphometric examination revealed cancellous osteopenia in FVIII KO mice as evidenced by decreased bone area and trabecular number and increased trabecular separation. Bone formation parameters were normal in FVIII KO mice. In contrast, osteoclast-lined bone perimeter was increased. These data demonstrate that bone disease in FVIII KO mice is due to an increased rate of bone resorption.

show abstract

Section: Introductionmentioning

confidence: 93%

The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The presence of these antibodies renders the replacement therapy ineffective with increased morbidity and mortality. [33][34][35] Experiences with protein replacement therapy demonstrate that manufacturing procedures, mismatches between the therapeutic protein sequence and host rare haplotypes, and modifications on the amino acid sequence could all influence the rates of inhibitor formation. 2,[36][37][38] Here we sought to test the safety of liver-restricted expression of the cFIX-Padua variant.…”

Section: Discussionmentioning

confidence: 99%

AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice

Crudele

Finn

Siner

et al. 2015

Blood

138

178

View full text Add to dashboard Cite

• Liver-restricted expression of FIX-Padua induces immune tolerance to the transgene in hemophilia B inhibitor dog models.• Long-term toxicity studies show no increased risk of thrombogenicity of FIX-Padua in mice and dogs.Emerging successful clinical data on gene therapy using adeno-associated viral (AAV) vector for hemophilia B (HB) showed that the risk of cellular immune response to vector capsid is clearly dose dependent. To decrease the vector dose, we explored AAV-8 (1-3 3 10 12 vg/kg) encoding a hyperfunctional factor IX (FIX-Padua, arginine 338 to leucine)in FIX inhibitor-prone HB dogs. Two naïve HB dogs showed sustained expression of FIX-Padua with an 8-to 12-fold increased specific activity reaching 25% to 40% activity without antibody formation to FIX. A third dog with preexisting FIX inhibitors exhibited a transient anamnestic response (5 Bethesda units) at 2 weeks after vector delivery following by spontaneous eradication of the antibody to FIX by day 70. In this dog, sustained FIX expression reached ∼200% and 30% of activity and antigen levels, respectively. Immune tolerance was confirmed in all dogs after challenges with plasma-derived FIX concentrate. Shortening of the clotting times and lack of bleeding episodes support the phenotypic correction of the severe phenotype, with no clinical or laboratory evidence of risk of thrombosis. Provocative studies in mice showed that FIX-Padua exhibits similar immunogenicity and thrombogenicity compared with FIX wild type. Collectively, these data support the potential translation of gene-based strategies using FIX-Padua for HB. (Blood. 2015;125(10):1553-1561

show abstract

“…1 Infusion of plasma-derived or recombinant FVIII is the standard treatment. Alloantibodies (inhibitors) that neutralize the protein-replacement therapy develop in 20% to 30% of young patients with severe and moderate hemophilia A, resulting in high morbidity and mortality, 2,3 and this is a growing problem for adults as well. 4,5 Risk factors for inhibitor formation include both genetic and environmental factors.…”

Section: Introductionmentioning

confidence: 99%

Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy

Finn

Ozelo

Sabatino

et al. 2010

Blood

140

173

View full text Add to dashboard Cite

Inhibitory antibodies to factor VIII (FVIII) are a major complication in the treatment of hemophilia A, affecting approximately 20% to 30% of patients. Current treatment for inhibitors is based on long-term, daily injections of large amounts of FVIII protein. Liver-directed gene therapy has been used to induce antigen-specific tolerance, but there are no data in hemophilic animals with pre-existing inhibitors. To determine whether sustained endogenous expression of FVIII could eradicate inhibitors, we injected adeno-associated viral vectors encoding canine FVIII (cFVIII) in 2 strains of inhibitor hemophilia A dogs. In 3 dogs, a transient increase in inhibitor titers (up to 7 Bethesda Units [BU]) at 2 weeks was followed by continuous decline to complete disappearance within 4-5 weeks. Subsequently, an increase in cFVIII levels (1.5%-8%), a shortening of clotting times, and a reduction (> 90%) of bleeding episodes were observed. Immune tolerance was confirmed by lack of antibody formation after repeated challenges with cFVIII protein and normal protein half-life. A fourth dog exhibited a strong early anamnestic response (216 BU), with slow decline to 0.8 BU and cFVIII antigen detection by 18 months after vector delivery. These data suggest that liver gene therapy has the potential to eradicate inhibitors and could improve the outcomes of hemophilia A patients. (Blood. 2010;116(26): 5842-5848) IntroductionThe development of neutralizing antibodies to replacement protein is a major complication of protein and enzyme replacement therapies for several genetic diseases. Hemophilia A is an X-linked bleeding disorder characterized by deficiency in the activity of factor VIII (FVIII), a key component of the coagulation cascade. The disease occurs in approximately 1 in 10 000 live births worldwide, and Ͼ 40% of these patients have severe disease, with FVIII activity Ͻ 1% of normal. 1 Infusion of plasma-derived or recombinant FVIII is the standard treatment. Alloantibodies (inhibitors) that neutralize the protein-replacement therapy develop in 20% to 30% of young patients with severe and moderate hemophilia A, resulting in high morbidity and mortality, 2,3 and this is a growing problem for adults as well. 4,5 Risk factors for inhibitor formation include both genetic and environmental factors. Underlying mutations in the FVIII gene, such as large gene deletions, nonsense mutations, and the most common mutation in severe hemophilia A patients, the inversion of intron 22, are all associated with inhibitor formation; however, it is not possible to predict with certainty which patients will develop inhibitors. For this reason, preventive strategies are not currently feasible. [6][7][8] Patients with high titers of inhibitors, defined as Ͼ 5 Bethesda units (BU), cannot usually be treated with FVIII replacement, necessitating the use of products that bypass the procoagulant effect of FVIII and are extremely expensive. 1 Thus, strategies for the eradication of inhibitors are of fundamental clinical relevance.Currently, the only pro...

show abstract

Delays in maturation among adolescents with hemophilia and a history of inhibitors

Cited by 14 publications

References 18 publications

The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption

The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption

AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice

Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy

Contact Info

Product

Resources

About