scholarly journals Activated factor X targeted stored in platelets as an effective gene therapy strategy for both hemophilia A and B

2021 ◽  
Vol 11 (3) ◽  
Author(s):  
Dawei Wang ◽  
Xiaohu Shao ◽  
Qiang Wang ◽  
Xiaohong Pan ◽  
Yujun Dai ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Hemophilia A ◽  
Factor X ◽  
Therapy Strategy ◽  
Gene Therapy Strategy

scholarly journals Analysis of the spatial and temporal characteristics of platelet-delivered factor VIII–based clots

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1101-1108 ◽  
Author(s):  
Michael Neyman ◽  
Jamie Gewirtz ◽  
Mortimer Poncz
Keyword(s):  
Gene Therapy ◽  
Hemophilia A ◽  
Temporal And Spatial Distribution ◽  
Laser Injury ◽  
Therapy Strategy ◽  
Spatial Differences ◽  
Gene Therapy Strategy ◽  
Platelet Accumulation ◽  
Temporal And Spatial ◽  
Spatial And Temporal Characteristics

Abstract Normally factor (F) VIII is not expressed in megakaryocytes, but when human FVIII was transgenically expressed in murine megakaryocytes, it was stored in platelet α-granules and released at sites of injury. This platelet FVIII (pFVIII) is effective in correcting hemostasis, even in the presence of circulating inhibitors, so it offers a potential gene therapy strategy for hemophilia A. To understand clot development by pFVIII, we have examined clot response to laser injury in both cremaster arterioles and venules in FVIIInull mice either infused with FVIII or transgenic for pFVIII. In both sets of vessels, pFVIII is at least as effective as infused FVIII. However, there are temporal and spatial differences in fibrin and platelet accumulation within clots depending on how FVIII is delivered. These differences may be related to the temporal and spatial distribution of the α-granular–released FVIII within the developing clot, and may explain the increased frequency and size of embolic events seen with pFVIII. These observations may not only have implications for the use of pFVIII in gene therapy for hemophilia A, but may also have physiologic consequences, explaining why many procoagulant factors are delivered both in the plasma and in platelet α-granules.

scholarly journals Gene therapy strategy of glomerulosclerosis.

Ensho ◽  
1998 ◽  
Vol 18 (4) ◽  
pp. 265-269
Author(s):  
Yasufumi Kaneda ◽  
Yoshitaka Isaka ◽  
Enyu Imai
Keyword(s):  
Gene Therapy ◽  
Therapy Strategy ◽  
Gene Therapy Strategy

scholarly journals Peritoneal Dialysis in the 21st Century: The Potential of Gene Therapy

2002 ◽  
Vol 13 (suppl 1) ◽  
pp. S117-S124
Author(s):  
Catherine M. Hoff ◽  
Ty R. Shockley
Keyword(s):  
Gene Therapy ◽  
Peritoneal Dialysis ◽  
Genetic Engineering ◽  
Genetic Manipulation ◽  
Membrane Damage ◽  
Peritoneal Membrane ◽  
Functional Changes ◽  
Therapy Strategy ◽  
Transfer Strategies ◽  
Gene Therapy Strategy

ABSTRACT. One of the greatest biotechnologic advances of the last 25 yr is genetic engineering—the ability to identify and isolate individual genes and transfer genetic elements between cells. Genetic engineering forms the basis of a unique biotechnology platform called gene therapy: an approach to treating disease through genetic manipulation. It is becoming clear that during peritoneal dialysis, the peritoneal membrane undergoes various structural and functional changes that compromise the dialyzing efficiency of the membrane and eventually lead to membrane failure. A gene therapy strategy based on genetic modification of the peritoneal membrane could improve the practice of peritoneal dialysis through the production of proteins that would be of therapeutic value in preventing membrane damage and preserving its dialyzing capacity. The peritoneal membrane can be genetically modified by either ex vivo or in vivo gene transfer strategies with a variety of potentially therapeutic genes, including those for anti-inflammatory cytokines, fibrinolytic factors, and antifibrotic molecules. These genes could be administered either on an acute basis, such as in response to peritonitis, or on an intermittent basis to maintain physiologic homeostasis and perhaps to prevent the adverse changes in the membrane that occur over time. The anticipated effect of a gene therapy strategy could be measured in maintenance of desired transport characteristics and in patients being able to remain on the therapy for longer periods of time without the negative outcomes. In summary, the use of a gene therapy strategy to enhance peritoneal dialysis is an innovative and exciting concept with the potential to provide new treatment platforms for patients with end-stage renal disease.

scholarly journals France plans national gene therapy strategy

Nature ◽  
1994 ◽  
Vol 372 (6505) ◽  
pp. 397-397
Author(s):  
Declan Butler
Keyword(s):  
Gene Therapy ◽  
Therapy Strategy ◽  
Gene Therapy Strategy

Targeting FVIII Expression to Platelets Induces Immune Tolerance in Hemophilia A Mice with or without Pre-Existing Anti-FVIII Immunity,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4170-4170
Author(s):  
Yingyu Chen ◽  
Erin L. Kuether ◽  
Jocelyn A. Schroeder ◽  
Robert R. Montgomery ◽  
David W. Scott ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
High Titer ◽  
Control Group ◽  
Hematopoietic Stem ◽  
Therapy Strategy ◽  
Inhibitory Antibodies

Abstract Abstract 4170 Our previous studies have shown that targeting FVIII expression to platelets (2bF8) can correct murine hemophilia A phenotype even in the presence of inhibitory antibodies. In the present study, we wanted to explore 1) whether platelets containing FVIII can act as an immunogen; and 2) whether platelet-derived FVIII can induce immune tolerance in a hemophilia A mouse model. To investigate whether platelets containing FVIII can act as an immunogen in hemophilia A mice, we infused transgenic mouse platelets with a level of platelet-FVIII of 6 mU/108 platelets to naïve FVIIInull mice weekly for 8 weeks. These platelets were between 30 to 50% of total platelets upon infusion and the levels of platelet-FVIII in the infused animals were 0.11 ± 0.01 mU/108 platelets (n = 6) one week after infusion. No anti-FVIII inhibitory antibodies were detected in the infused mice during the study course. All animals developed inhibitors following further challenged with recombinant human FVIII (rhFVIII) at a dose of 50 U/kg by intravenous injection weekly for 4 weeks, indicating that infusion of platelets containing FVIII does not trigger immune response in hemophilia A mice. To explore whether platelet-derived FVIII will act as an immunogen in the presence of primed spleen cells (from mice already producing inhibitory antibody), we co-transplanted splenocytes from highly immunized FVIIInull mice and bone marrow (BM) cells from 2bF8 transgenic mice into 400 cGy sub-lethal irradiated FVIIInull recipients. We monitored the levels of inhibitory antibodies in recipients for up to 8 weeks and found that inhibitor titers declined with time after transplantation. We then challenged co-transplantation recipients with rhFVIII and found that inhibitor titers in the control group co-transplantat of FVIIInull BM cells increased 103.55 ± 64.83 fold (n = 4), which was significantly more than the group receiving 2bF8 transgenic BM cells (14.34 ± 18.48, n = 5) (P <.05). The inhibitor titers decreased to undetectable in 40% of 2bF8 transgenic BM cells co-transplantation recipients even after rhFVIII challenge, indicating immune tolerance was induced in these recipients. To further explore the immune response in the lentivirus-mediated platelet-derived FVIII gene therapy of hemophilia A mice, we transduced hematopoietic stem cells from pre-immunized FVIIInull mice with 2bF8 lentivirus (LV) followed by syngeneic transplantation into pre-immunized lethally irradiated FVIIInull recipients and monitored the levels of inhibitor titers in recipients. After full BM reconstitution, platelet-FVIII expression was sustained (1.56 ± 0.56 mU/108platelets, n = 10), but inhibitor titers declined with time, indicating that platelet-derived FVIII does not provoke a memory response in FVIIInullmice that had previously mounted an immune response to rhFVIII. The t1/2 of inhibitor disappearance in 2bF8 LV-transduced recipients (33.65 ± 11.12 days, n = 10) was significantly shorter than in untransduced controls (66.43 ± 22.24 days, n = 4) (P <.01). We also transplanted 2bF8 LV-transduced pre-immunized HSCs into 660 cGy sub-lethal irradiated naïve FVIIInull mice. After BM reconstituted, recipients were assessed by platelet lysate FVIII:C assay and tail clip survival test to confirm the success of genetic therapy. Animals were then challenged with rhFVIII. Only 2 of 7 2bF8 LV-transduced recipients developed inhibitory antibodies (55 and 87 BU/ml), while all untransduced control developed high titer of inhibitors (735.50 ± 94.65 BU/ml, n = 4). In conclusion, our results demonstrate that 1) platelets containing FVIII are not immunogenic in hemophilia A mice; and 2) platelet-derived FVIII may induce immune tolerance in hemophilia A mice with or without pre-existing inhibitory antibodies. This tolerance induction would add an additional significant benefit to patients with platelet-derived FVIII gene therapy strategy because protein infusion could be administered in some special situations (e.g. surgery in which a greater levels of FVIII may be required) with minimized risk of inhibitor development. Disclosures: No relevant conflicts of interest to declare.

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