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Encapsulated polynucleotides and methods of use

A polynucleotide, ribozyme technology, used in immunology, inflammation and cancer therapy, to solve the problems of peripheral cell and tissue disease collateral damage, limit the application of viral therapeutics, hinder the efficacy of repeated systemic administration, etc.

Pending Publication Date: 2021-09-03
ONCORUS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These factors limit the utility of viral therapeutics in the treatment of metastatic cancers, as naturally occurring antiviral responses hinder the efficacy of the repeated systemic administration required to treat such cancers
Even in the absence of such obstacles, subsequent viral replication in non-diseased cells can lead to substantial extra-disease collateral damage to surrounding cells and tissues

Method used

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  • Encapsulated polynucleotides and methods of use
  • Encapsulated polynucleotides and methods of use
  • Encapsulated polynucleotides and methods of use

Examples

Experimental program
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Embodiment 1

[0255] Example 1: Engineering of Polynucleotide Constructs Encoding Replication Competent Viral Genomes

[0256] The autonomously replicating polynucleotide constructs described herein are engineered and generated using standard molecular biology and genetics techniques. Exemplary constructs encoding specific viruses and the corresponding cancers treated with these constructs are described in Tables 13, 14 and 15 below. However, an appropriate virus can be selected based on the desired properties of the virus and the properties of the cancer to be treated. Similarly, miRNA target sequence cassettes (miR TS) can be inserted at one or more locations in the viral genome to control replication of the encoded viral genome in normal non-cancerous cells while allowing replication in cancerous cells. Exemplary constructs are described throughout this disclosure. The constructed constructs are summarized in Table 8 below.

[0257] Table 8: Polynucleotide constructs encoding replicat...

Embodiment 2

[0260] Example 2: Design and Production of Plasmids Comprising Polynucleotide Constructs Encoding Replication Competent Viral Genomes

[0261] Poly(A), 5'hammerhead ribozyme and 3'delta hepatitis ribozyme were added by fusion PCR after SVV viral DNA was synthesized in Genscript and inserted into the base vector using Gibson assembly. The base vector is 2.4 kb in length and contains a minimal origin of replication and a kanamycin resistance cassette that has been optimized for use in mammalian cells ( Figure 31A ). The expression cassette is disclosed as SEQ ID NO:1. A similar vector was constructed against Coxsackievirus (CVA21) and was Figure 31B shown in . The CVA21 expression cassette is disclosed as SEQ ID NO:2.

Embodiment 3

[0262] Example 3: Design and production of NanoV constructs flanked by ITRs

[0263] To generate ITR-flanked NanoV constructs, the autonomously replicating polynucleotide construct was inserted into an expression cassette flanked by AAV-derived ITRs under the control of a tetracycline (Tet)-responsive promoter. Figure 17 A schematic diagram of the model NanoV construct is provided. The tetracycline-responsive promoter (TRE Tight) drives the expression of mCherry, which serves as a placeholder and can be replaced by an appropriate viral genome construct ( Figure 17 shown as OV). Tetracycline-controlled transactivator (tTA) expression is controlled by a constitutive promoter, in Figure 17Shown as UbCP in . The NanoV construct was inserted into the UL3 / 4 intergenic region of HSV-1 using the Gateway cloning system (Thermo Fisher) which allows rapid insertion of different NanoV cassettes. Addition of tetracycline to the medium causes Tet to bind to tTA, preventing expression...

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Abstract

The present disclosure relates to polynucleotides comprising a nucleic acid sequence encoding a replication competent viral genome, wherein the polynucleotide is capable of producing a replication competent virus when introduced into a cell by a non-viral delivery vehicle. The present disclosure further relates to the encapsulation of the polynucleotides and the use of the polynucleotides and / or particles for the treatment and prevention of cancer.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 62 / 760,422, filed November 13, 2018, the contents of which are hereby incorporated by reference in their entirety. [0003] Statement Regarding Sequence Listing [0004] The Sequence Listing associated with this application is provided in text format rather than a paper copy and is hereby incorporated by reference into this specification. The name of the text file containing the sequence listing is ONCR_014_01WO_ST25.txt. The text file is 23KB, created on November 13, 2019, and submitted electronically via EFS-Web. technical field [0005] The present disclosure relates generally to the fields of immunology, inflammation and cancer therapy. More specifically, the present disclosure relates to particle-encapsulated polynucleotides encoding replication-competent viral genomes. The present disclosure also relates to the treatment and prevention of prol...

Claims

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Application Information

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IPC IPC(8): C12N9/22C12N15/66C12N15/86C12N15/113
CPCC12N15/66C12N15/86C12N2770/32032C12N2770/32043A61K35/768C12N2830/50C12N2710/16643C12N2830/003C12N2310/141C12N2310/12C12N2310/14C12N15/113C12Y207/07006C12N15/88C07K14/005C07K14/54C07K16/2809A61K9/127A61P35/00C12N2770/32034A61K9/5123
Inventor 米切尔·H·菲尼尔爱德华·肯尼迪洛伦娜·勒纳
Owner ONCORUS INC
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