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Adenoassociated virus vectors for the treatment of mucopolysaccharidoses

A vector and variant technology, applied in the vector and nucleic acid sequence for the treatment of mucopolysaccharidosis type IIID or Sanfilippo syndrome D type, in the field of treatment of mucopolysaccharidosis, which can solve the problem of limiting the long-term efficacy of products, volume difficulties, and no Application of MPSⅢD and other issues

Active Publication Date: 2019-06-07
ESTEVE PHARMA SA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Other disadvantages of ERT include: 1) the difficulty of administering prolonged IV infusions of 1-3 hours in pediatric patients, many of whom suffer from psychiatric disorders, and 2) the potential for patients to be positive for antibodies to enzymes of unknown clinical significance fact, but may limit product long-term efficacy, and 3) high cost of treatment, which also includes the cost of home care
The larger the brain, the more difficult it is to cover the entire organ volume with intraparenchymal injections, and delivery to humans requires vector administration at multiple sites, making delivery technically challenging and requiring the development of specific surgical procedures
[0019] Although multiple therapeutic strategies have been developed for other forms of MPS III, none of the above approaches have been applied to MPS III D

Method used

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  • Adenoassociated virus vectors for the treatment of mucopolysaccharidoses
  • Adenoassociated virus vectors for the treatment of mucopolysaccharidoses
  • Adenoassociated virus vectors for the treatment of mucopolysaccharidoses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0192] Example 1: Construction of pAAV-CAG-hGNS

[0193] The CDS of human glucosamine (N-acetyl)-6-sulfatase (NCBI reference sequence: NM_002076.3) was used as starting material and chemically synthesized for the stated purpose (GeneArt; Life Technologies). Acceptance CDS were cloned in plasmid pMA-RQ(AmpR) flanked by MluI and EcoRI restriction sites at 5' and 3', respectively.

[0194] The MluI / EcoRI human glucosamine (N-acetyl)-6-sulfatase CDS fragment was excised from the pMA-RQ plasmid and subsequently cloned into the MluI and EcoRI restriction sites of the AAV backbone plasmid pAAV-CAG between. The resulting plasmid was named pAAV-CAG-hGNS (accession number DSM 32342). see figure 1 A and SEQ ID NO:5 in.

[0195] The AAV backbone plasmid pAAV-CAG used here has been previously generated and contains the ITR from the AAV2 genome, the CAG promoter and the polyA signal from rabbit β-globin, and a multiple cloning site for cloning the CDS of interest. The CAG promoter is a...

Embodiment 2

[0196] Example 2: Construction of pAAV-CAG-ohGNS-version 1

[0197] An expression cassette containing an optimized form of the glucosamine (N-acetyl)-6-sulfatase cDNA sequence (ohGNS) was designed and obtained. Sequence optimization to maximize the efficiency of N-acetylglucosamine 6-sulfatase protein production in humans to increase RNA stability by eliminating cryptic splice sites and RNA destabilizing sequence elements, adding RNA stabilizing sequence elements, Codon optimization and G / C content adaptation to avoid changes such as stable RNA secondary structure. The CDS of human glucosamine (N-acetyl)-6-sulfatase (NCBI reference sequence: NM_002076.3) was used as a starting point for sequence optimization.

[0198] The first optimized CDS (GeneArt; Life Technologies) was cloned in the plasmid pMA-T(AmpR) flanked by MluI and EcoRI restriction sites on the 5' and 3' sides, respectively.

[0199] The MluI / EcoRI optimized human glucosamine (N-acetyl)-6-sulfatase CDS fragment ...

Embodiment 3

[0200] Example 3: Construction of pAAV-CAG-ohGNS-version 2

[0201] Sequence optimization (DNA2.0 Inc) was performed on the CDS of human glucosamine (N-acetyl)-6-sulfatase (NCBI reference sequence: NM_002076.3). The optimized CDS was cloned in plasmid pJ204(AmpR) flanked 5' and 3' with MluI and EcoRI restriction sites, respectively.

[0202] The MluI / EcoRI optimized human glucosamine (N-acetyl)-6-sulfatase CDS fragment was excised from the pJ204 plasmid and subsequently cloned into the AAV backbone plasmid pAAV-CAG between the MluI and EcoRI restriction sites between. The resulting plasmid was named pAAV-CAG-ohGNS-version 2 (accession number DSM 32344). see image 3 A and SEQ ID NO:7 in.

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Abstract

The present invention provides new adeno-associated virus-derived vectors and pharmaceutical compositions containing the same for the treatment of lysosomal storage disorders and specially, for the treatment of mucopolysaccharidoses Type IIID.

Description

technical field [0001] The present invention relates to polynucleotides and vectors for the expression of proteins of interest and their use in gene therapy. The present invention also relates to vectors and vectors useful in the treatment of mucopolysaccharides (MPS), in particular mucopolysaccharides type IIID or Sanfilippo D syndrome nucleic acid sequence. Background technique [0002] Lysosomes are organelles found in the cytoplasm of animal cells that contain more than 50 hydrolytic enzymes that break down biomolecules during the recycling of damaged cellular components or after engulfing viruses and bacteria. This organelle contains several types of hydrolytic enzymes, including proteases, nucleases, glycosidases, lipases, phospholipases, phosphatases, and sulfatases. All enzymes are acid hydrolases. [0003] Lysosomal storage disorders (LSDs) are caused by genetic defects affecting one or more lysosomal enzymes. These genetic diseases are often caused by a deficie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N9/16C12N15/86
CPCC12N9/16C12Y301/06014C12N15/86A01K2217/075A01K2227/105A01K2267/0362C12N2750/14143C12N2830/15C12N2830/90A61P3/00A61K38/465A61K48/0066
Inventor 卡莱斯·罗加·莱哈维尔吉尼娅·A·奥里戈特-门敦卡法蒂玛·博希·图贝特
Owner ESTEVE PHARMA SA
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