Methods of treatment with virus-based gene therapy

A gene therapy, virus technology, applied in the field of treatment with virus-based gene therapy, can solve problems such as breakthrough bleeding, negative impact on daily life, and inconvenient cost

Pending Publication Date: 2022-04-19
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This has several disadvantages, including the cost and inconvenience of frequent prophylactic infusions (up to 3 times per week), the need to plan physical activity around peaks and troughs in clotting factor levels, and the potential for breakthrough bleeding
Despite management with alternative therapies, hemophilia B still has a considerable negative impact on the daily lives of affected individuals

Method used

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  • Methods of treatment with virus-based gene therapy
  • Methods of treatment with virus-based gene therapy
  • Methods of treatment with virus-based gene therapy

Examples

Experimental program
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Effect test

Embodiment 1

[0291] Example 1 - Whole-exome sequencing of patients treated with adeno-associated virus serotype 8-factor IX (AAV8-FIX) gene therapy reveals potential determinants of sustained transgene expression

[0292] The safety and kinetics of FIX gene therapy in patients with hemophilia B are investigated in a Phase I / II clinical trial to assess the effect of treatment on FIX activity levels and bleeding rates, and to monitor patients.

[0293] First-in-human phase I / II prospective multicenter open-label study (NCT01687608) using a non-randomized (unmixed single-arm study) single-ascending dose design to evaluate the FIX gene therapy construct FIX Padua gene therapy in patients with hemophilia Safety and kinetics in adults with disease B. The study was conducted according to the standards of Good Clinical Practice and the principles of the Declaration of Helsinki. Ethical approval was obtained from the institutional review boards of all clinical sites. The study protocol was sponso...

Embodiment 2

[0351] Example 2 - Increased immunogenicity of CpG-containing adeno-associated virus serotype 8 (AAV8) constructs may contribute to decreased transgene expression

[0352] AAV8 gene therapy has shown efficacy in clinical trials. However, an early spontaneous decline in transgene expression has been observed in some patients. It was hypothesized that an anti-AAV8-specific T cell response killed the transduced hepatocytes, resulting in a decrease in transgene expression and an increase in ALT and AST levels. To date, animal models have not shown a spontaneous decrease in transgene expression, making it difficult to analyze vector immunogenicity with respect to a decrease in transgene activity. Therefore, a murine model and a 3D bioreactor model using primary human hepatocytes were developed to assess the immunogenicity of AAV8 vectors. As a first use of the model, the impact of immune-activating CpG islands in the human FIX (huFIX) AAV8 vector (AAV8-huFIX) on the immunogenicit...

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Abstract

Methods for treating a patient with virus-based gene therapy that facilitate sustained transgene expression are provided. The methods comprise administering to the patient an inhibitor of an interleukin-6 (IL6) signaling pathway or an NCOR2 / SMRT histone deacetylation pathway, and a virus-based gene therapy vector. Also provided are methods for assigning a virus-based gene therapy to a patient, the method comprises by evaluating whether the patient has a mutation associated with reduced SMRT / NCOR2 protein function in the SMRT / NCOR2 gene or interleukin-6 receptor (IL-6R) Mutations in the gene associated with reduced IL-6R function determine whether the patient has a genotype that sensitizes the patient to persistent infections achieved by virus-based gene therapy vectors. If the patient has a mutation in the SMRT / NCOR2 gene associated with a reduced SMRT / NCOR2 protein function or a mutation in the IL-6R gene associated with a reduced IL-6R function, a virus-based gene therapy vector is assigned to the patient.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 864,404, filed June 20, 2019, and U.S. Provisional Patent Application No. 62 / 867,172, filed June 26, 2019, the contents of which are They are hereby incorporated by reference in their entirety for all purposes. [0003] funding statement [0004] This invention was made in part with government support under Grant No. NIH NHLBI RC3 HL103396-01 awarded by the National Institutes of Health. The government may have certain rights in this invention. Background technique [0005] Several clinical studies have demonstrated the use of DNA viral vectors derived from non-pathogenic adeno-associated virus (AAV) for the successful delivery of transgenes to patients in need of gene therapy, such as those with hemophilia B. AAV vector constructs are generated by replacing the viral gene with a therapeutic cassette consisting of a promoter, a transgene of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A61K38/37A61K39/395A61P7/00A61P7/04C07K14/745C07K16/24C07K16/28C12N15/86A61K31/573
CPCA61K39/3955A61K48/0008A61K48/005A61K38/37A61K31/573A61P7/00A61P7/04C07K16/248C07K16/2866C07K14/745C12N15/86C12N2750/14143
Inventor I·比利奇B·赖佩特
Owner TAKEDA PHARMA CO LTD
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