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Gene editing for hemophilia a with improved factor viii expression

A gene locus, coding technology, applied in the direction of factor VII, gene therapy, genetic engineering, etc., can solve problems such as impaired secretion of FVIII protein

Pending Publication Date: 2021-11-26
CRISPR THERAPEUTICS AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, removal of the B domain containing up to 18 N-linked glycosylation sites resulted in impaired secretion of FVIII protein

Method used

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  • Gene editing for hemophilia a with improved factor viii expression
  • Gene editing for hemophilia a with improved factor viii expression
  • Gene editing for hemophilia a with improved factor viii expression

Examples

Experimental program
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Effect test

Embodiment 1

[0408] Embodiment 1. A system comprising: a deoxyribonucleic acid (DNA) endonuclease or a nucleic acid encoding the DNA endonuclease; a guide RNA (gRNA) comprising a spacer sequence complementary to a host cell locus or a nucleic acid encoding the gRNA; and a donor template comprising a nucleic acid sequence encoding a synthetic FVIII protein, wherein the synthetic FVIII protein comprises a B domain surrogate, wherein the B domain surrogate comprises 0 to 9 N-linked sugars sylation sites and are 3 to about 40 amino acids in length.

Embodiment 2

[0409] Embodiment 2. The system of embodiment 1, wherein the B domain surrogate comprises 0 to 6 N-linked glycosylation sites.

Embodiment 3

[0410] Embodiment 3. The system of embodiment 2, wherein the B domain surrogate comprises 0 to 3 N-linked glycosylation sites.

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Abstract

Provided herein, in some embodiments, are materials and methods for treating hemophilia A in a subject ex vivo or in vivo. Also provided herein, in some embodiments, are materials and methods for knocking in a coding sequence encoding a synthetic FVIII having a B domain substitute into a genome.

Description

technical field [0001] The disclosure provided herein relates to materials and methods for the ex vivo and in vivo treatment of hemophilia A. Additionally, materials and methods for gene editing to modulate the expression, function or activity of coagulation proteins such as Factor VIII (FVIII) are provided. Background technique [0002] Hemophilia A (HemA) is caused by a genetic defect in the FVIII gene (F8), which results in low or undetectable levels of the FVIII protein in the blood. This leads to ineffective clot formation at the site of tissue damage, leading to uncontrolled bleeding that can be fatal if left untreated. Replacing missing or non-functional FVIII proteins is an effective treatment for HemA subjects and is the current standard of care. However, protein replacement therapy requires frequent intravenous administration of FVIII protein, which is inconvenient in adults, problematic in children, costly (>$200,000 / year), and can lead to rupture and bleedin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00C12N9/22C12N9/64C12N15/10
CPCC12N15/113C12N2310/20C07K14/755C12N9/22C12N15/52C12N15/907C12N15/85C12N15/88A61K48/005C12N2750/14143C12N15/90C12N15/102A61K48/00C12N2800/22A61K48/0058A61K48/0066C12N2310/141A61K48/0075
Inventor A.R.布鲁克斯
Owner CRISPR THERAPEUTICS AG