Genetics and molecular biology of haemophilias A and B

Green, P. M.; Montandon, A. J.; Giannelli, F.

doi:10.1097/00001721-199108000-00007

Cited by 42 publications

(32 citation statements)

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“…Similar findings can be found in the literature [5,8]. Table 5 shows a compilation of data from several studies.…”

Section: Discussionsupporting

confidence: 85%

Gene Mutations and Inhibitor Formation in Patients with Hemophilia B

Ljung¹

1995

Acta Haematol

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The nature of the mutation in the factor IX gene is an important factor in determining whether a patient with hemophilia B will develop an inhibitor. In a series of 62 Swedish families with hemophilia B, including 30 with the severe form, approximately one third of the families exhibiting deletions or nonsense mutations contained one member who developed an inhibitor. The risk for inhibitor development in family members carrying missense mutations was virtually zero.

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“…Similar findings can be found in the literature [5,8]. Table 5 shows a compilation of data from several studies.…”

Section: Discussionsupporting

confidence: 85%

Gene Mutations and Inhibitor Formation in Patients with Hemophilia B

Ljung¹

1995

Acta Haematol

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“…23,28,54 Animals with missense mutations generally did not form inhibitory antibodies to canine F.IX after intramuscular vector injection (except at high doses), whereas animals with an early stop codon routinely developed inhibitory antibodies to AAV vectorencoded canine F.IX even at low doses. This finding is consistent with older observations 55 derived from studies of patients with hemophilia B treated with clotting factor concentrates, which demonstrated that individuals with missense mutations virtually never develop inhibitory antibodies, whereas those with mutations that result in substantial loss of coding information (eg, gene deletions, early stop codons) have a risk of inhibitor formation considerably higher than the hemophilia population as a whole. It is important to note that, in dogs with hemophilia B due to an early stop codon, inhibitory antibodies could be elicited even at vector doses too low to result in detectable circulating levels of F.IX.…”

Section: Absence Of Antibodies To Fixsupporting

confidence: 91%

AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B

Manno

Chew

Hutchison

et al. 2003

Blood

696

561

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Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (F.IX). Previously, we established an experimental basis for gene transfer as a method of treating the disease in mice and hemophilic dogs through intramuscular injection of a recombinant adeno-associated viral (rAAV) vector expressing F.IX. In this study we investigated the safety of this approach in patients with hemophilia B. In an open-label dose-escalation study, adult men with severe hemophilia B (F.IX < 1%) due to a missense mutation were injected at multiple intramuscular sites with an rAAV vector. At doses ranging from 2 ؋ 10 11 vector genomes (vg)/kg to 1.8 ؋ 10 12 vg/ kg, there was no evidence of local or systemic toxicity up to 40 months after injection. Muscle biopsies of injection sites performed 2 to 10 months after vector administration confirmed gene transfer as evidenced by Southern blot and transgene expression as evidenced by immunohistochemical staining. Preexisting high-titer antibodies to AAV did not prevent gene transfer or expression. Despite strong evidence for gene transfer and expression, circulating levels of F.IX were in all cases less than 2% and most were less than 1%. Although more extensive transduction of muscle fibers will be required to develop a therapy that reliably raises circulating levels to more than 1% in all subjects, these results of the first parenteral administration of rAAV demonstrate that administration of AAV vector by the intramuscular route is safe at the doses tested and effects gene transfer and expression in humans in a manner similar to that seen in animals. (Blood.

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“…9 This is a substantial shortcoming in the hemophilia B disease model, because mice and humans with large deletions of F.IX have a propensity for formation of inhibitory antibodies on exposure to F.IX protein. 10,11 The formation of these antibodies makes it impossible to track the results of a therapeutic intervention. Moreover, a model in which inhibitory antibody formation is likely to occur, while providing a stringent screen, does not provide a reliable indication of the likelihood of inhibitor formation in the setting of mutations that involve less-extensive loss of coding information.…”

Section: Introductionmentioning

confidence: 99%

Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene

Sabatino

Armstrong

Edmonson

et al. 2004

Blood

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Animal models have been critical to the development of novel therapeutics in hemophilia. A deficiency of current murine models of hemophilia B is that they are all due to gene deletions, a type of mutation that is relatively rare in the human hemophilia population. We generated mice with a range of mutations in the Factor IX (F.IX) gene; these more faithfully reflect the types of mutations that cause disease in the human population. Transgenic mice expressing either wild-type human F.IX (hF.IX), or F.IX variants with premature translation termination codons, or missense mutations, under the control of the murine transthyretin promoter, were generated and crossed with mice carrying a large deletion of the murine F.IX gene. Gene copy number, F.IX transcript levels in the liver, intrahepatocyte protein expression, and circulating levels of F.IX protein in the mice were determined and compared with data generated by transient transfection assays using the same F.IX variants. Mice were injected with a viral vector expressing hF.IX and displayed a range of immune responses to the transgene product, depending on the underlying mutation. These new mouse models faithfully mimic the mutations causing human disease, and will prove useful for testing novel therapies for hemophilia.

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Genetics and molecular biology of haemophilias A and B

Cited by 42 publications

References 0 publications

Gene Mutations and Inhibitor Formation in Patients with Hemophilia B

Gene Mutations and Inhibitor Formation in Patients with Hemophilia B

AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B

Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene

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