Pharmaceutical composition comprising Nanog shRNA, and method of using Nanog shRNA to treat cancer
Inventors
Jessup, John Milburn • Korokhov, Nikolay
Assignees
US Department of Health and Human Services
Publication Number
US-9512429-B2
Publication Date
2016-12-06
Expiration Date
2031-12-06
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Abstract
The present description relates to an inhibitory RNA molecule, comprising an oligonucleotide that selectively knocks down expression a Nanog pseudogene expressed in many human cancers, a replicating viral vector capable of encoding such inhibitory RNA molecule, pharmaceutical compositions comprising said vector, and methods of treating cancer by administration of said pharmaceutical composition.
Core Innovation
The invention relates to inhibitory RNA molecules comprising oligonucleotides that selectively knock down expression of Nanog or Nanog pseudogenes, particularly NanogP8, which are expressed in many human cancers. It includes viral vectors encoding such RNA molecules, pharmaceutical compositions comprising these vectors, and methods of treating cancer by administering these compositions.
The problem addressed is the high cancer-specific mortality associated with colorectal carcinoma (CRC) and the need for effective therapeutics to prevent and treat CRC. Nanog and its pseudogenes, including NanogP8, are implicated in cancer stem cell properties, tumor development, and metastasis, but their roles in tumorigenesis and metastasis progression in various cancers remain unclear.
The invention provides allele-specific shRNAs that knock down Nanog or NanogP8 expression selectively without interfering with the other, allowing targeted inhibition. Viral vectors, such as lentiviruses and conditionally replicating adenoviruses (CRAd), are engineered to deliver these inhibitory RNAs to cancer cells, especially colorectal cancer cells, to induce apoptosis, inhibit proliferation, and reduce tumor mass. A CRAd is specifically designed with a NANOGP8 promoter controlling viral replication, thus targeting cells expressing NanogP8 for virus replication and oncolysis.
Claims Coverage
The patent includes multiple claims, with at least one independent claim describing a conditionally replicating viral vector with specific inhibitory RNA molecules. Below is the summary of the main inventive features disclosed in the independent claims.
Conditionally replicating viral vector comprising NanogP8-targeted inhibitory RNA molecules
The invention provides a conditionally replicating viral vector comprising an inhibitory RNA molecule with an oligonucleotide sequence selected from specific shRNA sequences (SEQ ID NO:3, NO:37, NO:8, NO:34) that knock down expression of NanogP8.
Viral vector inducing apoptosis, inhibiting proliferation, and reducing tumor mass
The viral vector is capable of inducing apoptosis of cancer cells, inhibiting cancer cell proliferation, and reducing tumor mass when administered.
Viral vector with specific coat protein targeting malignant cells expressing Ad5/3 receptors
The viral vector is packaged in a coat protein that specifically binds to malignant cells expressing receptors for Ad5/3 chimeric fibritins, including leukemias, sarcomas, and carcinomas such as colorectal carcinoma cells.
Viral vector overexpressing RNA inhibiting NanogP8 expression
The viral vector overexpresses an RNA inhibitory molecule that targets and inhibits expression of NanogP8.
Use of minimal promoter comprising adenovirus E1a gene and NANOGP8 promoter
The viral vector includes a minimal promoter operatively linked to the inhibitory RNA molecule, comprising a portion of the adenovirus E1a gene and a portion of the NANOGP8 promoter, enabling conditional viral replication in NanogP8-expressing cells.
The viral vector may be adenovirus, measles virus, or herpes simplex virus based
The viral vector may be a conditionally replicating adenovirus (CRAd), measles virus, or herpes simplex virus vector.
Pharmaceutical composition comprising the viral vector
The patent claims a pharmaceutical composition comprising the aforementioned viral vector and a pharmaceutically acceptable carrier.
Method of treating colorectal cancer using the viral vector
A method of treating colorectal cancer (CRC) by administering a therapeutically effective amount of a conditionally replicating viral vector carrying inhibitory RNA molecules targeting Nanog or NanogP8, with sequences selected from SEQ ID NO:3, NO:37, NO:8, or NO:34.
The claims define the inventive features as conditionally replicating viral vectors targeting NanogP8 with specific inhibitory RNA sequences, capable of inducing apoptosis and tumor growth inhibition, with selective targeting via viral coat proteins and controlled replication using a NANOGP8 promoter, formulated into pharmaceutical compositions and used in colorectal cancer treatment.
Stated Advantages
The viral vector induces apoptosis of cancer cells.
The viral vector inhibits cancer cell proliferation.
The viral vector reduces tumor mass.
Documented Applications
Treatment of colorectal carcinoma (CRC) via administration of pharmaceutical compositions containing viral vectors encoding inhibitory RNA molecules targeting Nanog or NanogP8.
Use of viral vectors to inhibit growth and metastasis of colorectal cancer cells expressing NanogP8.
Delivery of allele-specific shRNAs to cancer cells to selectively knock down Nanog or NanogP8 expression.
Use of conditionally replicating adenoviruses (CRAd) selectively replicating in NanogP8-expressing tumor cells for oncolytic therapy.
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