In vivo gene therapy using delivery of a lentiviral gene construct

A lentiviral vector and delivery technology, used in gene therapy, medical materials derived from viruses/phages, genetic engineering, etc.

Pending Publication Date: 2021-01-26
SEATTLE CHILDRENS HOSPITAL (DBA SEATTLE CHILDRENS RES INST)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Despite previous studies, there remains a need for safe and reliable methods of replacing or supplementing functional FVIII in subjects

Method used

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  • In vivo gene therapy using delivery of a lentiviral gene construct
  • In vivo gene therapy using delivery of a lentiviral gene construct
  • In vivo gene therapy using delivery of a lentiviral gene construct

Examples

Experimental program
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Effect test

example 1

[0126] Example 1. Improving the therapeutic efficacy of in vivo platelet-targeted gene therapy for hemophilia A

[0127] A previously described in vivo hematopoietic stem cell (HSC)-based platelet-targeted gene therapy protocol partially corrected the bleeding phenotype in hemophilia A (HemA) mice over five months. In the described protocol, a lentiviral vector (LV) carrying a factor III (FVIII) transgene (G-F8 / N6-LV) driven by a megakaryocyte-specific promoter (Gp1bα) is delivered by intraosseous (IO) infusion to transduce HSCs. Maturation of HSCs transduced along the megakaryocyte lineage leads to ectopic FVIII production in platelets. However, there is still a need for an effective and clinically feasible protocol to improve LV transduction efficiency and increase platelet-FVIII function.

[0128] To enhance LV transduction, this example describes a combination drug regimen of dexamethasone and anti-CD8α monoclonal antibody, followed by IO infusion of LV in mice. In M-GF...

example 2

[0178] Example 2. Intraosseous delivery of lentivirus as a therapeutic strategy for in vivo gene therapy for hemophilia

[0179] As described above, lentiviral vectors (LV) delivered by intraosseous (IO) infusion at precisely controlled rates can efficiently transduce bone marrow hematopoietic stem cells (HSCs) in mice. Infusion of LV IO carrying a human FVIII / N6 transgene driven by a platelet-specific Gp1bα promoter into hemophilia A (HemA) mice produced FVIII stored in platelet alpha granules. These platelet FVIII partially corrected the bleeding phenotype over five months in HemA mice with or without pre-existing anti-FVIII inhibitors.

[0180] In the present example, LV IO delivery was applied to humanized NSG mice to establish a translational research model for in vivo gene therapy in hemophilia. First, it was examined whether high levels of transgene expression could be achieved in human megakaryocytes (Meg). Human CD34 was transduced with Cocal-MND-GFP-LV (M-GFP-LV, M...

example 3

[0185] Example 3. Intraosseous delivery of lentivirus produces human platelet-specific Factor VIII in humanized NSG mice

[0186] This example establishes a proof-of-principle research model in humanized NSG mice for the translational application of this novel strategy in the human clinic.

[0187] Hemophilia A (HemA) lacking functional plasma factor VIII (FVIII) is an ideal candidate disease for gene therapy to achieve long-term therapeutic FVIII levels.

[0188] This article describes a new clinically translatable strategy for the treatment of HemA. In this strategy, a self-inactivating lentiviral vector (LV) carrying a FVIII transgene driven by the platelet-specific promoter Gp1bα(G) (G-FVIII-LV) was passed intraosseously ( 10) Administration delivery into HemA mice. G-FVIII-LV can effectively transduce hematopoietic stem cells (HSC). Then, FVIII specifically expressed and stored in platelet α-granules could partially correct the bleeding phenotype over five months in im...

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Abstract

Methods, compositions, and systems for treating subject(s) in need of plasma Factor VIII, particularly a subject having preexisting anti-FVIII inhibitory antibodies, are provided. The methods involveadministering to the subject a therapeutically effective amount of an inflammation suppressor, a therapeutically effective amount of a CD8+ T cell depleting agent, and a therapeutically effective amount of a composition comprising a lentiviral vector (LV) comprising an optimized FVIII expression cassette expressibly linked to a megakaryocyte-specific promoter. Such methods, compositions, and systems are useful to treat subjects with blood clotting disorder(s), such as hemophilia A.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 62 / 663,930, filed April 27, 2018, which is hereby incorporated by reference in its entirety as if fully set forth herein. [0003] Statement Regarding Federally Sponsored Research or Development [0004] This invention was made with government support under Grant Nos. HL123326-01A1 and HL134621-01 awarded by NIH / NHLBI. The government has certain rights in this invention. technical field [0005] The present disclosure provides compositions and methods for in vivo gene therapy, eg, using intraosseous delivery or other modes of delivery. An example of such therapy provides platelet-specific expression of enhanced plasma Factor VIII activity, eg, for the treatment of hemophilia and other blood clotting disorders. Background technique [0006] Inhibitory antibody formation against human factor VIII (FVIII) is an important complication in the treatme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K38/37C12N15/00A61K31/56A61K48/00
CPCA61K38/37A61K45/06A61K35/76A61K31/573C07K16/2815A61K39/3955A61K2300/00A61P7/04A61K48/0058A61K48/0075
Inventor C·H·苗D·J·罗林斯C·李
Owner SEATTLE CHILDRENS HOSPITAL (DBA SEATTLE CHILDRENS RES INST)
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