Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs

Russell, Karen E.; Olsen, Eva H. N.; Raymer, Robin A.; Merricks, Elizabeth P.; Bellinger, Dwight A.; Read, Marjorie S.; Rup, Bonita; Keith, James C.; McCarthy, Kyle P.; Schaub, Robert G.; Nichols, Timothy C.

doi:10.1182/blood-2003-05-1498

Cited by 37 publications

(39 citation statements)

References 26 publications

(31 reference statements)

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“…Indeed, injecting hFVIII into newborn mice resulted in tolerization to protein challenge when they became adults, 62 whereas initiating frequent injections of hFIX at birth led to the development of tolerance in HB dogs from Chapel Hill. 63 These results provide a rationale for testing whether frequent administration of factor immediately after birth can reduce the frequency of inhibitor formation in patients at high risk for their development. *Number of animals with antibodies was determined out of the total number evaluated.…”

Section: Neonatal Gene Transfer Results In Tolerance For Hb 149mentioning

confidence: 99%

Neonatal gene transfer with a retroviral vector results in tolerance to human factor IX in mice and dogs

Zhang

Haskins

et al. 2004

Blood

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The effect of neonatal gene transfer on antibody formation was determined using a retroviral vector (RV) expressing human factor IX (hFIX). Normal mice from different strains injected intravenously with RV as newborns achieved therapeutic levels of hFIX without antibody production and were tolerant as adults to challenge with hFIX. Neonatal hemophilia B mice that received different amounts of RV achieved stable and dose-related expression of hFIX without anti-hFIX antibody formation. After protein challenge, antibody formation was markedly reduced for animals that expressed hFIX at levels higher than 14 ng/mL (0.3% of normal). However, antibodies developed for animals that received the lowest dose of RV and expressed hFIX at approximately 2 ng/mL before protein challenge.

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Section: Neonatal Gene Transfer Results In Tolerance For Hb 149mentioning

confidence: 99%

Neonatal gene transfer with a retroviral vector results in tolerance to human factor IX in mice and dogs

Zhang

Haskins

et al. 2004

Blood

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“…Control untreated HA and HB dogs that were observed concurrently within this study exhibited 12 and 21 spontaneous bleeds in 36 and 60 cumulative months of observation, respectively (Table 2). In a cumulative 34 months (HB) and 45 months (HA) of observation, the AAV8-cFVIIa treated dogs did not exhibit any spontaneous bleeding episodes, in contrast to the expected 15 (HB) and 21 (HA) episodes (P Ͻ .002 vs historical data in this dog colony 27,28 or the paired concurrent controls; Table 2). The lowest dosed HB dog exhibited 3 nonspontaneous bleeds within the first 8 months after AAV vector administration and each after a hemostatic challenge (the initial surgery for vector delivery, a liver biopsy performed to study cFVIIa expression, and dog fighting; normal canine plasma was administered daily for each episode for up to 3 days).…”

Section: Aav-cfviia-treated Hemophilic Dogs Do Not Exhibit Spontaneoumentioning

confidence: 99%

“…Because dogs with hemophilia exhibit approximately 5 or 6 spontaneous bleeding episodes per year, 27,28 we used the number of spontaneous bleeds as a clinically relevant efficacy endpoint. Control untreated HA and HB dogs that were observed concurrently within this study exhibited 12 and 21 spontaneous bleeds in 36 and 60 cumulative months of observation, respectively (Table 2).…”

Section: Aav-cfviia-treated Hemophilic Dogs Do Not Exhibit Spontaneoumentioning

confidence: 99%

Successful treatment of canine hemophilia by continuous expression of canine FVIIa

Margaritis

Roy

Aljamali

et al. 2009

Blood

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103

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“…If, as has been proposed, most of the bloodborne TF comes from leukocyte-derived microparticles (14), the difference in platelet counts may be of limited concern in interpretation of results. The effect of continuously expressed FVIIa on frequency of joint bleeds will perhaps be better assessed in a canine model of hemophilia, where observation of animals over many years has established a baseline number of readily diagnosed bleeds, including joint bleeds, in untreated animals (26). Improvement of hemostasis in a large-animal model has previously been a strong predictor of efficacy of products in human subjects (27)(28)(29).…”

Section: Figurementioning

confidence: 99%

Long-term expression of murine activated factor VII is safe, but elevated levels cause premature mortality

Aljamali

Margaritis²,

Schlachterman³

et al. 2008

J. Clin. Invest.

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Intravenous infusion of recombinant human activated Factor VII (FVIIa) has been used for over a decade in the successful management of bleeding episodes in patients with inhibitory antibodies to Factor VIII or Factor IX. Previously, we showed that expression of murine FVIIa (mFVIIa) from an adeno-associated viral (AAV) vector corrected abnormal hemostatic parameters in hemophilia B mice. To pursue this as a therapeutic approach, we sought to define safe and effective levels of FVIIa for continuous expression. In mice transgenic for mFVIIa or injected with AAV-mFVIIa, we analyzed survival, expression levels, in vitro and in vivo coagulation tests, and histopathology for up to 16 months after birth/mFVIIa expression. We found that continuous expression of mFVIIa at levels at or below 1.5 μg/ml was safe, effective, and compatible with a normal lifespan. However, expression levels of 2 μg/ml or higher were associated with thrombosis and early mortality, with pathologic findings in the heart and lungs that were rescued in a low-factor X (low-FX) mouse background, suggesting a FX-mediated effect. The findings from these mouse models of continuous FVIIa expression have implications for the development of a safe gene transfer approach for hemophilia and are consistent with the possibility of thromboembolic risk of continuously elevated FVIIa levels.

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Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs

Cited by 37 publications

References 26 publications

Neonatal gene transfer with a retroviral vector results in tolerance to human factor IX in mice and dogs

Neonatal gene transfer with a retroviral vector results in tolerance to human factor IX in mice and dogs

Successful treatment of canine hemophilia by continuous expression of canine FVIIa

Long-term expression of murine activated factor VII is safe, but elevated levels cause premature mortality

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