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Delivery of autologous cells comprising matrix metalloproteinase for treatment of scleroderma

A matrix metal and protease technology, applied in the direction of medical preparations containing active ingredients, animal cells, skin diseases, etc., can solve the problem of heavy treatment work, long-term prevention of long-term active disease or recurrence, dosage regimen or frequency and total Issues such as lack of consensus on exposure

Pending Publication Date: 2020-02-07
PRECIGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the combination of methotrexate and systemic corticosteroids is effective in the early stages of the disease, it does not prevent long-term active disease or relapse in the long term (Piram et al., 2013)
[0009] UVA1 phototherapy may be effective; however, treatment can be burdensome (2-3 sessions per week for 30-40 sessions) and the recurrence rate after treatment is 46% (Piram et al., 2013)
Although most researchers agree that UVA1 is an effective treatment for localized scleroderma, there is little consensus on dosing regimen or frequency and total exposure

Method used

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  • Delivery of autologous cells comprising matrix metalloproteinase for treatment of scleroderma
  • Delivery of autologous cells comprising matrix metalloproteinase for treatment of scleroderma
  • Delivery of autologous cells comprising matrix metalloproteinase for treatment of scleroderma

Examples

Experimental program
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Effect test

example 1

[0122] Construction and characterization of LV-RTS-MMP1 lentivirus

[0123] The recombinant lentiviral vector (LV) LV-RTS-MMP1 was used to introduce the MMP1 gene into cultured fibroblasts. The LV is a non-replicating vesicular stomatitis virus-G (VSV-G) pseudotyped, self-inactivating (3rd passage) lentivirus (SIN-LV). LV-RTS-MMP1 has a nucleotide sequence corresponding to SEQ ID NO:1, and an amino acid sequence has a sequence of SEQ ID NO:3.

[0124] Source of human MMP1 gene

[0125]The sequence of MMP1 cDNA (SEQ ID NO:1) was derived from the consensus sequence of human pro-MMP1, wherein the native MMP1 signal peptide was replaced by the signal peptide sequence (SEQ ID NO:2) of human pigment epithelium-derived factor (PEDF) to provide More efficient secretion of MMP1 from fibroblasts. The cDNA (1410 bp) was generated and cloned into standard expression plasmids for initial analysis. The MMP1 cDNA was then engineered to remove potential splice sites and cloned into th...

example 2

[0126] Example 2: FCX-013 and Veledimex background

[0127] 2.1 In vitro studies

[0128] Veledimex-induced expression of MMP1 was assessed in primary fibroblasts genetically modified by transduction with LV-RTS-MMP1. Primary normal human dermal fibroblasts (NHDF) were transduced with different dilutions of research grade LV-RTS-MMP1 stock solution. Two passages after transduction, transduced NHDFs (HDF-RTS-MMP1 ) were seeded into 24-well plates and treated with 100 nM veledimex or 0.1% DMSO (vehicle). The study also included NHDF not transduced with LV-RTS-MMP1 ("mock"). Cell supernatants were collected 72 hours after addition of veledimex or DMSO and analyzed for MMP1 expression levels by ELISA (R&D Systems DuoSet). Cells were collected and analyzed for integrated LV-RTS-MMP1 copy number (average per cell) by qPCR using primers and a probe specific for the LV-RTS-MMP1 construct. The results of the three transduction studies are detailed in Table 2 below, and in Figur...

example 3

[0145] Example 3: Studies in NOD / SCID mice

[0146] This example describes studies using a bleomycin-induced (BLM-induced) disease model in NOD / SCID mice. Figure 8 An overview of the progress of the treatment is shown.

[0147] Table 5 provides a description of the study groups.

[0148] The design of this study was based on experimental data (data not shown) which showed that:

[0149] In NOD / SCID mice given FCX-013 plus veledimex, MMP1 expression (both protein and mRNA) was maximal between 24 hours and 3 days and was undetectable at 28 days after FCX-013 injection.

[0150] Protein expression was higher in BLM-treated animals compared to non-BLM-treated animals.

[0151] The observed systemic toxicity was attributed to bleomycin treatment.

[0152] No established toxicity with 2x 10 6 FCX-013 cell related

[0153] On day 10 after injection of FCX-013, DNA copy number and MMP1 expression decreased rapidly

[0154] To ensure adequate MMP1 expression, copy number target...

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Abstract

The present invention relates to a method for the treatment of scleroderma through the delivery of matrix metalloproteinase (MMP) to a patient in need thereof, preferably under the control of a gene switch. In this manner, the use of a ligand activator to activate or deactivate the expression of MMP controls the gene switch. In another embodiment, the invention is directed to the delivery of autologous genetically modified cells transfected / transduced with a polynucleotide encoding MMP under the control of a gene switch activatable through the use of an activator ligand for the treatment or scleroderma.

Description

[0001] References to Sequence Listings [0002] This application contains a Sequence Listing that has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on April 20, 2018, is named "INX00372WO_Sequence_Listing_20180420.txt" and is 11,691 bytes in size (12,288 bytes on disk). technical field [0003] The present invention relates to methods and compositions for treating scleroderma by delivering polynucleotides encoding matrix metalloproteinases (MMPs) or collagen-degrading fragments thereof to patients in need thereof. In another embodiment, the present invention relates to the delivery of a polynucleotide encoding an MMP in a vector to cells isolated from a patient with sclerosis, where it is conditionally expressed by using a gene switch expression system. The cells are preferably isolated from a patient, transfected with a polynucleotide encoding an MMP, cultured in vitro or ex vivo, and then administ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/435C07K14/705C07K16/28A61K35/36A61K38/17C12N9/50C12N9/64C12N5/07
CPCA61K35/36C12N9/6491C12Y304/24007A61K38/48C12N15/86A61K31/166A61K9/0014A61K9/0019A61K9/0021A61K9/0024A61K9/0043A61K9/0053A61K9/06A61K9/08A61K9/10A61K47/42A61K9/48A61K48/005A01K2207/20A01K2227/105A01K2267/0306C12N2740/16043A61P17/00A61K2300/00A61K38/00A61K38/4886C07K16/28A61P19/04A61K31/15A61K35/33
Inventor D·托马斯J·马斯洛斯基A·马尔亚拉
Owner PRECIGEN INC
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