Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy

Samelson-Jones, Ben; Arruda, Valder R.

doi:10.1016/j.omtm.2018.12.007

Cited by 44 publications

(51 citation statements)

References 226 publications

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“…The reported specific activity of human and canine FIX-R338L ranges between 5-and 15-fold higher than the FIX-WT ortholog, depending on the reagents and source of protein, with about 8-fold being the most consistently observed (reviewed in ref. 6), which is in agreement with our clotting assay results. However, the procoagulant advantages of FIX/FIXa-R338L over FIX/FIXa-WT that we observed were assay dependent, with the clotting assay specific activity being about 8-fold while the determined EC 50 of the TGA parameters ranged from 3-to 10-fold.…”

Section: Discussionsupporting

confidence: 92%

“…Steroids have been effective in reducing the loss of transgene expression in most, but not all, AAV liver-directed gene therapy trials (reviewed in ref. 6).…”

Section: Introductionmentioning

confidence: 99%

“…Hepatotoxicity, as defined by elevated liver enzymes, has been observed in at least some subjects in all AAV gene transfer trials for HB (2,(4)(5)(6)(7) as well as for hemophilia A (HA; ref. 8).…”

Section: Introductionmentioning

confidence: 99%

“…these AAV-related hepatotoxicities, including the use of transgenes with advantageous properties (6). To this end, the high specific activity FIX variant R338L (FIX-R338L; Padua; ref.…”

Section: Introductionmentioning

confidence: 99%

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Hyperactivity of factor IX Padua (R338L) depends on factor VIIIa cofactor activity

Samelson-Jones¹,

Finn²,

George³

et al. 2019

JCI Insight

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Section: Discussionsupporting

confidence: 92%

“…Steroids have been effective in reducing the loss of transgene expression in most, but not all, AAV liver-directed gene therapy trials (reviewed in ref. 6).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…these AAV-related hepatotoxicities, including the use of transgenes with advantageous properties (6). To this end, the high specific activity FIX variant R338L (FIX-R338L; Padua; ref.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Hyperactivity of factor IX Padua (R338L) depends on factor VIIIa cofactor activity

Samelson-Jones¹,

Finn²,

George³

et al. 2019

JCI Insight

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“…Another relevant question is the discrepancy in FVIII and FIX activity assays. Differences in factor activity measurement have been observed using the standard one‐stage clotting assays and chromogenic assays in patients with haemophilia A who received an AAV vector expressing a B‐domain deleted FVIII transgene, and similarly, in patients with haemophilia B who were infused with an AAV vector carrying F9 cDNA with Padua variant . These discrepancies preclude reliable interpretation of factor activity measurements in order to determine the potency of the final product and provide substantial evidence of effectiveness for a marketing application; the Scientific and Standardization (SSC) Committee of the International Society on Thrombosis and Haemostasis (ISTH) needs to provide recommendations on coagulation assays to detect FVIII and FIX activity.…”

Section: Resultsmentioning

confidence: 99%

Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia

Peyvandi

Garagiola

2019

Haemophilia

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Replacement therapy of the deficient coagulation factor using plasmaderived or recombinant concentrates is the mainstay of treatment for patients with haemophilia A and B, the most severe bleeding disorders. 1 Significant improvements have been achieved through the production of novel extended half-life products or non-replacement therapies. 2 These new drugs could overcome current prophylaxis limitations by reducing dosing frequency and changing the routes of administration (from intravenous infusions to subcutaneous injections), thereby improving compliance and rendering therapy less distressing for the patient. 3 A definitive cure for haemophilia may lie in gene therapy.Haemophilia A and B are an ideal target for gene therapy because both are monogenic disorders caused by genetic defects in the F8 and F9 genes, respectively. In addition, a modest increase in clotting factor activity (>1 IU/dL) can substantially attenuate bleeding risk, and even treatment efficacy can be assessed easily by routine laboratory assay. AbstractGene therapy is rapidly becoming a new therapeutic strategy for haemophilia A and B treatment. In the 1990s, studies in animal models showed that adeno-associated vectors (AAV) exhibited an efficient expression of factor IX (FIX). In the first clinical trial in patients with haemophilia B, therapeutic levels of FIX were documented but the expression remained only for few weeks. Subsequently, improvements in vector design, such as the use of different AAV serotypes, the development of the self-complementary vector, the engineering of the transgene with codon optimization and liver-specific expression cassette resulted in circulating FIX level between 2% and 5% for long-lasting period. Recently, a natural gain of function FIX variant (Padua) inserted in the F9 cDNA improved the expression of FIX achieving a level of more than 30% resulting in cessation of infusions and in a greatly reduction of bleeding events.Encouraging clinical progresses have been also obtained from trials of gene therapy for haemophilia A. Transgene expression persisted for three years with circulating FVIII activity levels of 52.3% in patients treated with AAV vector containing a codonoptimized F8 cDNA. A complication, reported in both clinical trials for haemophilia A and B, was the elevation of liver enzymes, which resolved with steroid treatment in a large group of patients. However, to date, the pathophysiological mechanism for the liver toxicity remains still unclear. Clinical trials with adeno-associated vectors have documented a significant success for haemophilia gene therapy demonstrating potential to transform haemophilia treatment offering hope for a long-term expression. K E Y W O R D Sadeno-associated virus, clinical trials, factor IX, factor VIII, gene therapy, haemophilia

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Generation of hyperfunctional recombinant human factor IX variants expressed in human cell line SK-Hep-1

et al. 2020

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Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy

Cited by 44 publications

References 226 publications

Hyperactivity of factor IX Padua (R338L) depends on factor VIIIa cofactor activity

Hyperactivity of factor IX Padua (R338L) depends on factor VIIIa cofactor activity

Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia

Generation of hyperfunctional recombinant human factor IX variants expressed in human cell line SK-Hep-1

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