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Optimized mini-dystrophin genes and expression cassettes and their use

A muscle-atrophic, small-scale technology, applied in gene therapy, peptide/protein components, chemical instruments and methods, etc., can solve the problem of DMD patients being helpful

Active Publication Date: 2019-04-16
BAMBOO THERAPEUTICS INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the mechanisms of action of these drugs are not expected to be helpful in all DMD patients, and further evidence is needed to definitively demonstrate their clinical efficacy in DMD

Method used

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  • Optimized mini-dystrophin genes and expression cassettes and their use
  • Optimized mini-dystrophin genes and expression cassettes and their use
  • Optimized mini-dystrophin genes and expression cassettes and their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0416] Synthesis of codon-optimized human small dystrophin gene

[0417] We previously generated small versions of many human dystrophin genes by PCR cloning of human muscle dystrophin cDNA, resulting in a C with a large deletion in the central rod domain and an almost complete deletion of the dystrophin coding sequence. Small dystrophin gene in the terminal region (Wang et al., Proc. Natl. Acad. Sci., USA 97:13714 (2000); US Patent Nos. 7,001,761 and 7,510,867). These small dystrophin genes were tested to be highly functional in vivo in the DMD mdx mouse model (Watchko et al., Human Gene Therapy 13:1451 (2002)). One of these small dystrophic proteins, named Δ3990, is described in US Patent No. 7,510,867 as SEQ ID NO:6. The protein sequence of Δ3990 and the DNA encoding it are provided herein as SEQ ID NO:27 and SEQ ID NO:28, respectively.

[0418] Modifications to the Δ3990 mini-dystrophin were also designed, codon optimized and tested for activity. The new small human dys...

Embodiment 2

[0433] CMV-Hopti-Dys3978 in dystrophin / dystrophin-related protein double knockout mice

[0434] Loss of dystrophin in Duchenne muscular dystrophy (DMD) patients leads to devastating skeletal muscle degeneration and cardiomyopathy. Mdx mice lacking only dystrophin have a milder phenotype, whereas double knockout (dKO) mice lacking both dystrophin and its cognate dystrophin-related protein exhibit the clinical symptoms similar to those of severe malnutrition. It has been previously demonstrated that with 3 × 10 11 Intraperitoneal injection of vg / mouse AAV1-CMV-Δ3990 (not codon-optimized) into neonatal homozygous dKO mice partially restored growth, function and extended lifespan by several months (50% survival at 22 weeks rate) (see from Wang et al., J.Orthop.Res, 27:421 (2009) Figure 6B ). Here, AAV9 was used as a capsid to assess the therapeutic effect of systemic delivery of the human codon-optimized Hopti-Dys3978 gene. The results showed that the AAV9-CMV-Hopti-Dys3978 ...

Embodiment 3

[0443] hCK-Hopti-Dys3978 in mdx mice

[0444] To examine whether the hybrid synthetic muscle-specific promoter hCK could effectively drive Dys3978 gene expression, this promoter was compared to the same construct driven by a non-specific CMV strong promoter. Immunofluorescent staining of small dystrophin expression in mdx mice following tail vein injection of the corresponding vectors revealed that both promoters, hCK and CMV, delivered equal expression levels in muscle and heart ( Figure 10 ).

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Abstract

This invention relates to polynucleotides encoding mini-dystrophin proteins, viral vectors comprising the same, and methods of using the same for delivery of mini-dystrophin to a cell or a subject.

Description

[0001] Statement Regarding Federally Sponsored Research and Development [0002] This invention was made with government support under Grant Numbers AR050595, AR056394, and AR056953 awarded by the National Institutes of Health. The government has certain rights in this invention. technical field [0003] The present invention relates to a polynucleotide encoding a mini-dystrophin protein, a viral vector comprising the polynucleotide, and a method for delivering mini-dystrophin protein to a cell or a subject using the viral vector method. Background technique [0004] Duchenne muscular dystrophy (DMD) is a severe, X-linked, progressive neuromuscular disorder that affects approximately 1 in 3,600 to 9,200 male births. The disorder is caused by a frameshift mutation in the dystrophin gene that disrupts expression of the dystrophin protein. Premature death results from the degeneration of skeletal and eventually cardiac and respiratory muscles (eg, intercostal and diaphragm m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/47
CPCC07K14/4708C12N15/86A01K67/0278A61K48/0058A61K45/06A61K38/1709A61P21/00C12N2750/14143C12N2800/22C12N2830/008A01K2267/0306A01K2227/105A01K2217/075A01K2227/10C07K14/78
Inventor 史考特·W·J·麦克菲乔春平李娟肖啸马里查·麦金太尔理查·J·萨谬斯基
Owner BAMBOO THERAPEUTICS INC
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