Gene therapy for haemophilia

Sharma, Akshay; Mathew, Minu; Sriganesh, Vasumathi; Reiss, Ulrike

doi:10.1002/14651858.cd010822.pub3

Cited by 9 publications

(4 citation statements)

References 51 publications

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“…Gene therapy has previously identified potential candidates for the treatment of human diseases including cancer, cardiovascular disease, blood diseases, diabetes, genetic diseases and other diseases that cannot be treated with conventional drug therapies (50)(51)(52). Previously, the use of viral vectors to deliver vectors to express functional genes has been applied in different medical fields, including cancer therapy and cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Recombinant adenovirus expressing a dendritic cell‑targeted melanoma surface antigen for tumor‑specific immunotherapy in melanoma mice model

Guo

Wang

et al. 2018

Exp Ther Med

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Abstract. Viral vectors represent a potential strategy for the treatment of human malignant tumors. Currently, recombinant adenovirus vectors are commonly used as gene therapy vehicles, as it possesses a proven safety profile in normal human cells. The recombinant adenovirus system has an ability to highly express exogenous genes and increase the stability of the carrier, which is only transiently expressed in the host cell genome, without integrating. Malignant melanoma cells are produced by the skin, and melanocyte tumors that exhibit higher malignant degrees lead to earlier transfer and higher mortality. In the present study, a recombinant adenovirus (rAd) was generated to express Anti-programmed death-1 (rAd-Anti-PD-1) and used to investigate the efficacy in melanoma cells and tumors. The results demonstrated that B16-F10 cell growth was significantly inhibited and the apoptosis incidence rate was markedly promoted following rAd-PD-1 treatment. The present study demonstrated that the production of α and β interferon was increased, which led to the induction of dendritic cell (DCs) maturation in rAd-anti-PD-1-treated mice. The present study indicated that rAd-anti-PD-1 exhibited the ability to generate more cluster of differentiation (CD)4 + CD8 + T cells and induce a PD-1-specific cytotoxic T lymphocyte through DC-targeted surface antigens in mice. This resulted in a further enhanced recognition of melanoma cells due to DCs being targeted by the rAd-anti-PD-1-encoded PD-1. Notably, mice treated with the rAd-anti-PD-1-targeted PD-1 demonstrated an improved protection compared with tumor-bearing mice from the challenge group treated with a recombinant gutless adenovirus and Anti-PD-1. In conclusion, the present study demonstrated that targeting the melanoma surface antigens via the rAd-anti-PD-1-infected tumor cells enhanced the ability of recombinant adenovirus to induce a potent tumor-inhibitory effect and antigen-specific immune response.

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Section: Discussionmentioning

confidence: 99%

Recombinant adenovirus expressing a dendritic cell‑targeted melanoma surface antigen for tumor‑specific immunotherapy in melanoma mice model

Guo

Wang

et al. 2018

Exp Ther Med

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“…Moreover, we are reminded that the current array of single arm, primarily Phase 1/2 gene therapy trials serve as first in man proof of principle studies that place us squarely at the beginning of the evidenced‐based clinical research agenda in gene therapy. As a recent Cochrane Systematic Review concluded: “Gene therapy for haemophilia is still in its nascent stages and there is need for well‐designed clinical trials to assess the long‐term feasibility, success and risks … for people with haemophilia.” 15 To that end, efforts are underway at the NHLBI within the NIH in the United States to assist the hemophilia community in configuring the mechanistic research requirements and clinical scientific priorities that would inform the future landscape of the most challenging gene therapy trials for individuals with hemophilia A and FVIII inhibitors.…”

Section: Gene Therapy At the Forefront Of Therapeutic Progressmentioning

confidence: 99%

“…for people with haemophilia." 15 To that end, efforts are underway at the NHLBI within the NIH in the United States to assist the hemophilia community in configuring the mechanistic research requirements and clinical scientific priorities that would inform the future landscape of the most challenging gene therapy trials for individuals with hemophilia A and FVIII inhibitors.…”

Section: Gene Therapy At the Forefront Of Therapeutic Progressmentioning

confidence: 99%

Navigating Speed Bumps on the Innovation Highway in Hemophilia Therapeutics

DiMichele

2018

HemaSphere

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The unprecedented emergence of novel therapeutics for both hemophilia A and B during the last half decade has been accompanied by the promise of even more extraordinary progress in ameliorative and curative strategies for both disorders. Paradoxically, the speed of innovation has created new dilemmas for persons with hemophilia and their physicians with respect to optimizing individual choices from the expanding menu of standard and novel therapies and approaches to symptom or risk reduction, and ultimately, to normalizing the hemophilia phenotype. Among the most disruptive new approaches, challenges remain in the form of the adverse reactions that have been observed with nonfactor therapies, as well as in the uncertain long-term safety profile of potentially curative gene therapy. Together, these challenges have generated uncertainty as to how to adopt novel therapies and treatment strategies across a diverse patient population, creating speed bumps on the hemophilia innovation highway. It is from this perspective that this article discusses the current state of gene therapy and bleeding prophylaxis for hemophilia A and B, as well as prevention and treatment of the factor VIII inhibitor phenotype in hemophilia A. It further posits that these speed bumps may provide important clues to the mechanistic understanding of both symptom manifestation and resilience within the hemophilia phenotype, as well as opportunities to reconsider and reconfigure the current paradigms for symptom prediction and individualized therapeutic decision making.

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“…As an alternative, direct infusion of complementary FIX DNA into hemophilia B animals and patients through viral delivery was evaluated, and it has proven to be efficacious 3, 4. The clinical trials by Nathwani and colleagues5, 6, 7 showed long-term therapeutic FIX expression after gene transfer of an adeno-associated virus (AAV) vector based on serotype 8 (AAV8) for the treatment of 10 patients with severe hemophilia B. However, the duration of expression is still under consideration, as the AAV vector predominantly persists episomally in host cells.…”

Section: Introductionmentioning

confidence: 99%

Viral Vector-Based Delivery of CRISPR/Cas9 and Donor DNA for Homology-Directed Repair in an In Vitro Model for Canine Hemophilia B

Gao

Bergmann

Zhang

et al. 2019

Molecular Therapy - Nucleic Acids

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Gene therapy represents an attractive alternative to treat hemophilia B. Here we established three hepatocyte-derived cell lines based on Huh7, PLC/PRF/5, and Hep3B cells stably carrying a mutated canine FIX (cFIXmut) transgene containing a single point mutation in the catalytic domain. Based on these in vitro models resembling a commonly used canine large animal model, the tetracycline-controlled transcriptional activator (Tet-on)-inducible CRISPR/Cas9 system and an optimized donor were used to correct mutated cFIX gene through homology-directed repair (HDR). For efficient delivery of designer nuclease and donor DNA, we produced a high-capacity adenovirus vector type 5 (HCAdV5) containing the Tet-on-inducible cFIX-specific CRISPR/Cas9 system and a single-stranded adeno-associated virus type 2 vector (ssAAV2) containing the modified donor. Moreover, we designed a single HCAdV5 delivering all components for HDR. Our amplification-refractory mutation system based on qPCR analysis (ARMS-qPCR) revealed that the single vector application in Huh7-cFIXmut cells resulted in up to 5.52% HDR efficiencies, which was superior to the two-vector strategy. Furthermore the single vector also resulted in increased phenotypic correction efficiencies assayed by ELISA. We conclude that HDR in combination with viral vector delivery holds great promise for the correction of mutated FIX in disease models.

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Gene therapy for haemophilia

Cited by 9 publications

References 51 publications

Recombinant adenovirus expressing a dendritic cell‑targeted melanoma surface antigen for tumor‑specific immunotherapy in melanoma mice model

Recombinant adenovirus expressing a dendritic cell‑targeted melanoma surface antigen for tumor‑specific immunotherapy in melanoma mice model

Navigating Speed Bumps on the Innovation Highway in Hemophilia Therapeutics

Viral Vector-Based Delivery of CRISPR/Cas9 and Donor DNA for Homology-Directed Repair in an In Vitro Model for Canine Hemophilia B

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