Extravascular administration of factor IX: potential for replacement therapy of canine and human hemophilia B.

Liles, Darla; Cn, Landen; Monroe, DM; Cm, Lindley; Ms, Read; Roberts, Howard W.; Km, Brinkhous

doi:10.1046/j.1365-2516.1997.t01-1-00125.x

Cited by 19 publications

(28 citation statements)

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“…A series of studies that administer the FIX protein subcutaneously have been reported in animals and humans with dosing that ranges from 15 to 200 IU/kg. [23][24][25] All these studies detected measurable FIX in the recipient's plasma following subcutaneous administration. In the study by Liles et al, 25 a single adult patient with hemophilia B (cross-reacting material negative, CRMϪ) given a high-purity plasma-derived hFIX subcutaneously developed a transient, low titer inhibitor (1-2 Bethesda units) months after the clinical study while being treated for a traumatic bleed.…”

Section: Discussionmentioning

confidence: 89%

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

Russell¹,

Olsen

Raymer

et al. 2003

Blood

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Section: Discussionmentioning

confidence: 89%

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

Russell¹,

Olsen

Raymer

et al. 2003

Blood

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“…34,35 Therefore, an extended pharmacokinetic Figure 4. Representative histopathologic findings at 2 weeks after joint bleeding challenge.…”

Section: Ia Fix Does Not Increase Circulating Fix Activitymentioning

confidence: 99%

Intraarticular factor IX protein or gene replacement protects against development of hemophilic synovitis in the absence of circulating factor IX

Sun

Hakobyan

Valentino

et al. 2008

Blood

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Hemophilic bleeding into joints causes synovial and microvascular proliferation and inflammation (hemophilic synovitis) that contribute to end-stage joint degeneration (hemophilic arthropathy), the major morbidity of hemophilia. New therapies are needed for joint deterioration that progresses despite standard intravenous (IV) clotting factor replacement. To test whether factor IX within the joint space can protect joints from hemophilic synovitis, we established a hemophilia B mouse model of synovitis. Factor IX knockout (FIX ؊/؊ ) mice received a puncture of the knee joint capsule with a needle to induce hemarthrosis; human factor IX (hFIX) was either injected through the needle into the joint space (intraarticu- larly IntroductionThe most significant morbidity resulting from congenitally deficient factor VIII or IX activity (hemophilia A or hemophilia B) is the progressive destruction of joints resulting from recurrent intraarticular (IA) hemorrhage. Although bleeding at other sites does occur in persons with hemophilia, the musculoskeletal system is by far the most common site; 85% of all bleeding events occur in joints, and 80% of these affect 6 problem joints: the elbows, knees, and ankles. 1 Joint hemorrhage is treated by intravenous (IV) infusion of clotting factor to raise the circulating plasma activity. There is a need for adjunctive therapies directed specifically to the pathology within the hemophilic joint.An understanding of the pathophysiology of hemophilic joint disease is only now emerging. [2][3][4] Joint bleeding results in a chronic inflammatory disorder known as hemophilic synovitis, which in time evolves into a complex arthritis termed hemophilic arthropathy, in which the synovial disease is accompanied by degenerative changes in cartilage and underlying bone. 3,4 As the inflammatory environment that develops in response to blood in a joint stimulates neoangiogenesis of fragile blood vessels, one or more "target" joints for recurrent bleeding develop. Joint-surface erosions secondary to chronic synovitis often occur in early childhood. 5 If aggressive early prophylactic factor replacement is not instituted, 90% of persons with severe hemophilia (Ͻ 1% factor VIII or factor IX activity) will have chronic degenerative changes in 1 to 6 joints by 25 years of age.A limited number of treatment options exist for recurrent joint bleeding and hemophilic synovitis. 6 The mainstay of therapy is replacement clotting factor dosed to achieve a circulating plasma activity level adequate to provide hemostasis throughout the body. Factor replacement in response to ongoing bleeding does not halt the progression of existing arthropathy. 5 Instead, institution of uninterrupted preventive (prophylactic) factor infusions at an early age, before the onset of recurrent joint bleeding, should be the standard of care. 7 The major costs of hemophilia to the healthcare system in dollars, to society in lost productivity and to the person with hemophilia in terms of quality of life, result from bleeding into joints. 8 F...

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“…31 Rapid uncoating has been recently proposed as a mechanism for efficient liver transduction in mouse liver by AAV8 vectors. 32 Similar mechanisms may also apply to AAV8 or AAV5 transduction in canine liver, since C52, which received AAV2/5 vector, also had the peak expression at day 7.…”

Section: Hepatic Gene Therapy In Hemophilia B Dogs Bymentioning

confidence: 99%

Sustained correction of disease in naive and AAV2-pretreated hemophilia B dogs: AAV2/8-mediated, liver-directed gene therapy

Wang

Calcedo

Nichols

et al. 2005

Blood

159

147

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Adeno-associated virus 8 (AAV8), a new member of the AAV family isolated from nonhuman primates, is an attractive candidate for hepatic gene transfer applications because of 10-to 100-fold improved transduction efficiency in mouse liver models. Additionally, AAV8 has lesser frequency of pre-existing immunity in humans. These properties could solve some of the problems associated with AAV2 vectors. The benefits of AAV8 demonstrated in mouse models, however, have not been confirmed in larger animals. In this study, we evaluate the efficacy and safety of AAV2/8 vector in both naive and AAV2-pretreated hemophilia B dogs. Two naive hemophilia B dogs that received a single intraportal administration of AAV2/8 vector have achieved sustained expression of 10% and 26% of normal levels of canine factor IX (cFIX) for more than a year. In an AAV2-pretreated hemophilia B dog, cFIX expression increased from less than 1% to 16% of normal levels when

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Extravascular administration of factor IX: potential for replacement therapy of canine and human hemophilia B.

Cited by 19 publications

References 0 publications

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

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

Intraarticular factor IX protein or gene replacement protects against development of hemophilic synovitis in the absence of circulating factor IX

Sustained correction of disease in naive and AAV2-pretreated hemophilia B dogs: AAV2/8-mediated, liver-directed gene therapy

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